AU2008201198A1 - Endothelin anatagonists - Google Patents

Description

S&F Ref: 493447D3

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: The following statement is a full performing it known to me/us: Abbott Laboratories, of CHAD 0377/AP6D-2 100 Abbott Park Road, Abbott Park, Illinois, 60064-3500, United States of America 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, Martin Winn, Steven J. Wittenberger, Thomas W. von Geldern Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Endothelin antagonists description of this invention, including the best method of 5845c(1163198_1) WO 99/06397 PCT/US98/15479 00 ENDOTHELIN ANTAGONISTS This is continuation-in-part application of U.S. patent application Serial No. 08/905,913, filed August 4, 1997 which is a continuation-inpart of U.S. patent application Serial No. 08/794,506, filed February 4, oo 1997 which is a continuation-in-part of U.S. patent application Serial No. 08/600,625, filed February 13, 1996, which is a continuation-in- Spart of U.S. patent application Serial No. 08/497,998, filed August 2, N 10 1995, which is a continuation-in-part of U.S. patent application Serial 00 0 No. 08/442,575, filed May 30, 1995, which is a continuation-in-part of 0 U.S. patent application Serial No. 08/334,717, filed November 4, 1994, which is a continuation-in-part of U.S. patent application Serial No.

08/293,349, filed August 19, 1994.

Technical Field The present invention relates to compounds which are endothelin antagonists, processes for making such compounds, synthetic intermediates employed in these processes and methods and compositions for antagonizing endothelin.

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

It has been shown that vasoconstriction is caused by binding of endothelin to its receptors on vascular smooth muscle (Nature 332 411 WO 99/06397 PCT/US98/15479 00 0(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 oo 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 l 10 effects of intravenously administered cyclosporin (Kon, et al., Kidney 0 Int. 3Z 1487 (1990)) and attenuated infarct size in a coronary artery Sligation-induced myocardial infarction model (Watanabe, et al., Nature 344 114 (1990)).

Clozel et al. (Nature 365: 759-761 (1993)) report that Ro 46- 2005, a nonpeptide ET-A/B antagonist, prevents post-ischaemic renal vasoconstriction in rats, prevents the decrease in cerebral blood flow due to subarachnoid hemorrhage (SAH) in rats, and decreases MAP in sodium-depleted squirrel monkeys when dosed orally. A similar effect of a linear tripeptide-like ET-A antagonist, BQ-485, on arterial caliber after SAH has also been recently reported (S.ltoh, T. Sasaki, K. Ide, K.

Ishikawa, M. Nishikibe, and M. Yano, Biochem. Biophys. Res. Comm. 969-75 (1993). These results indicate that agents which antagonize ET/ET receptor binding will provide therapeutic benefit in the indicated disease states.

Agents with the ability to antagonize ET/ET receptor binding have been shown to be active in a number of animal models of human disease.

For example, Hogaboam et al (EUR. J. Pharmacol. 1996, 309, 261-269), have shown that an endothelin receptor antagonist reduced injury in a rat model of colitis. Aktan et al (Transplant Int 1996, 9, 201-207) have demonstrated that a similar agent prevents ischemia-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 WO 99/06397 PCT/US98/15479 00 0 00 oN 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 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.

lo Disclosure of the Invention In accordance with the present invention there are compounds of the formula R2

R

3

(CH

2 n

R

wherein Z is -C(R 1 8

)(R

1 9 or wherein R 18 and R 19 are independer 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, -P0 3

H

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

-CN,

-C(O)NHR17 wherein R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(0) 2

R

1 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, itly (yl, WO 99/06397 PCT/US98/15479 00 (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, HO 0 0 00 So HO 0 00 OH 0 0 0 0

()H

NI0 Jill)-CF 3

N

Mt H ,or

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, WO 99/06397 PCTIUS98/15479 00 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 5 R 2 is other than hydrogen; R 3 is R 4

-C(O)-R

5 R-a R 4

R

5

-N(R

6

R

6

-S(O)

2

-R

7 00 or R 26

-S(O)-R

27 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20

)-R

8 or -R 8 a-N(R 20

)-R

8 N' 10 wherein R8 and RBa are independently selected from 00 0 the group consisting of alkylene and alkenylene 0 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 R9a are independently selected from alkylene; is alkylene or (ii) alkenylene;

R

7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-Rlo- or -RlOa-N(R21)-R10 wherein Rio and Rioa are independently selected from the group consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl;

R

4 and R 6 are independently selected from the group consisting of (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from hydrogen, loweralkyl, haloalkyl, -alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic,

A_

WO 99/06397 MS1/57 00 (12) arylalkyl, CI(13) (heterocyclic)alkyl, (14) hydroxyalkyl, alkoxy, 5 (16) aminoalkyl, (17) trialkylaminoalkyl, 00 (18) alkylaminoalkyl,.

(19) dialkylaminoalkyl, and 5(20) carboxyalkyl, Nl 10 (i i) loweralkyl, 0ii0lknl 0 (iii) alkynyl, 0(iv) cyalkyl, (vi) cycloalkylal, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (heterocyclic)alkyt, (x i) alkoxyalkyl, (x ii) hydroxyalkyl, (x i ii) haloalkyl, (xiv) haloalkeny!, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, (xix) dialkylaminoalkyl, (xx) alkoxy, and

(CH

2 )zN (Xxi) 0 wherein z is 0-5 and R7a is alkylene;

R

26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, -7 WO 99/06397 -PCT/US98/15479' 00 (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

25 00 wherein R 2 5 is alkylene and R 24 is hydrogen or loweralkyl, loweralkyl, N 10i alkenyl, 00 0 alkynyl, 0 cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, or

R

13 -C(O)-CH(Rl 4 wherein R 13 is amino, alkylamino or dialkylamino and R 1 4~ is aryl or R1 5 wherein R 15 is amino, alkylamino or dial kylImin o; or a pharmaceutically acceptable salt thereof.

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

N

(CH

2 )n

R

WO 99/06397 -8- PCT/US98/15479 00

O

O wherein the substituents -R 2 -R and -R 1 exist in a trans,trans relationship and Z, n, R, Ri, R 2 and R 3 are as defined above.

Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0 and Z is -CH 2 oo Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 1 and Z is -CH 2 0 o10 Another preferred embodiment of the invention is a compound of 0 formula or (II) wherein n is 0, Z is -CH 2 and R 3 is R 4

-C(O)-R

5

SR

6 -S(0) 2

-R

7 or R 26

-S(O)-R

27 wherein R 4

R

5

R

6

R

7

R

2 6 and R 27 are as defined above.

1i Another preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R 3 is alkoxyalkyl or alkoxyalkoxyalkyl.

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

-C(O)-R

5 wherein R 4 is (R11)(R 12 as defined above and R 5 is alkylene or R 3 is

R

6 -S(0) 2

-R

7 or R 26

-S(O)-R

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

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

)-R

8 or Re-S(0) 2

-N(R

2 1 )-Rlo- wherein R 8 and Rio are alkylene and R 4

R

6

R

20 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

16 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 aryl wherein aryl is phenyl substituted WO 99/06397 PCT/US98/15479 00 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 alkylsulfonylamidoalkyl, and R 3 is R 4

-C(O)-R

5 wherein R4 is (Ri 1 )(Rl 2 wherein R 11 and R 1 are independently 00 selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl, and Rq is alkylene; or R 3 is R4-C(O)-N(R 20

)-R

8 or

R

6

-S(O)

2

-N(R

2 1 )-Rl 0 wherein R 4 is loweralkyl, aryl, alkoxy, 00 alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, 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 R 26

-S(O)-R

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

A yet more preferred embodiment of the invention is a compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein Ri 6 is loweralkyl, haloalkyl or aryl, Z is -CH 2 R1 is loweralkyl, (ii) a Ike nyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl, (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethyiphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,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 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

20

)-R

8 or R6-S(O) 2

-N(R

21 )-Rlo- wherein R 8 and R 10 are alkylene, R 20 and R 21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, -10- WO 99/06397 -10- PCT/US98/I 5479 00 0 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 00 NHS(O) 2

R

16 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, 0 0 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, I,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 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)-R

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

)N-

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

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

NHS(O)

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

RI

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 WO 99/06397 PCT/US98/15479 00 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 (Rll)(Ri 2 wherein R 11 is loweralkyl and R 12 is aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, or heterocyclic.

Another yet more preferred embodiment of the invention is a 00 compound of formula or (11) wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or NHS(0) 2

R

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

RI

0 0 aryloxyalkyl, arylalkyl, (vi) (N-alkanoyl-N-alkyl)aminoalkyl, or (vii) alkylsulfonylamidoalkyl,(vii) phenyl, or (ix) substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3fIu o ro ph enyl, 3-f luoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy- 1,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen and R 3 is

R

6 -S(0) 2

-N(R

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

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

R

16 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 R1 is substituted or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4-methoxymethoxyphenyl, 1 ,3-benzodioxolyl o r 1 ,4-benzodioxanyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy and alkoxyalkoxy, (ii) loweralkyl, (iii) alkenyl, (iv) -12- WO 99/06397 PCT/US98/15479 00 heterocyclic (alkyl), aryloxyalkyl, (vi) arylalkyl, (vii) (N-alkanoyl-Nalkyl)aminoalkyl, (viii) alkylsulfonylamidoalkyl,or (ix) phenyl, R 2 is substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, B-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the 00 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 R 10 is alkylene, R 6 is haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl.

00 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 or haloalkyl, Z is -OH 2 Ri is Ioweralkyl,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 R4 is (Rll)(Rl 2 wherein R 11 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

RI

6 wherein

R

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 WO 99/06397 -13- PCTIUS98/15479 00

R

1 an 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trial kylamni noa lkyl, 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 00 NHS(0) 2

R

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

R

1 is loweralkyl, alkenyl, heterocyclic (alkyl), aryloxyalkyl, arylalkyl, (Nalkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, phenyl, or 0 0 dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(0)-R 5 wherein R5 is alkylene and R 4 is (Rll)(Rl 2 wherein R 11 and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, 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(0)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,

R

2 is 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(0)-R 5 wherein R5 is alkylene and R 4 is (Rii)(R 1 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(0)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-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the WO 99/06397 -14- PCT/US98/15479 00 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 5 (Rll)(Rl 2 wherein R 11 is loweralkyl and R 1 is aryl.

00 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 -0H2-, R1 is substituted N io or unsubstituted 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3- 00 0 fluorophenyl, 2-fluorophenyl, 3-fluoro-4-ethoxyphenyl, 4c-i 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 u nsubstituted 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

10 wherein Rio is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 is loweralkyl, haloalkyl or alkoxyalkyl.

Another most highly preferred embodiment of the invention is a compound 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 Rl 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 IRS is alkylene and R 4 WO 99/06397 -15- PCT/US98/1 5479 00 Sis (R11)(R 12 wherein R 11 is alkyl and R 12 is selected from aryl, aminoalkyl, trialkylaminoalkyl, and heterocyclic.

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

R

1 is oo loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (Nalkanoyl-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (R11)(R 12 wherein R 1 1 N 10 and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, 00 0 alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic, with the Sproviso that one or R 11 and R 1 is alkyl.

Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 and R3 is 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 loweralkyl, and R 3 is R4-C(O)-R 5 wherein R 4 is (R11)(R1 2 as defined therein and R5 is alkylene.

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 R 3 is R 4

-C(O)-R

5 wherein R4 is (R11)(R1 2 as defined therein and 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 R 3 is R4-C(O)-R 5 wherein R 4 is (R11)(R12)Nas 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 aryloxyalkyl, and R 3 is R 4

-C(O)-R

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

-1fi- WO 99/06397 PCT/US98/1547Y 00

O

C

N Another most highly preferred embodiment of the invention is a Scompound 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 (Rll)(R 12 as defined 5 therein and R 5 is alkylene.

oo Another most highly preferred embodiment of the invention is a compound of formula or (II) wherein n is 0, Z is -CH 2 R1 is aryl, and

R

3 is R 4

-C(O)-R

5 wherein R 4 is (R11)(R 12 as defined therein and Rs is alkylene.

oo 00 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 R4-C(O)-R 5 wherein R 4 is (R11)(R 12 as defined therein and R 5 is alkylene.

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

-C(O)-R

5 wherein R 4 is (R11)(R 12 as defined therein and Rs is alkylene.

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

The present invention also relates to a method of antagonizing endothelin in a mammal (preferably, a human) in need of such 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 WO 99/06397- 17- PCT/US98/15479 00 Sof the compounds of the invention are included in the present invention.

SThe terms and configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure S 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 oo 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" cl 10 pp. 152-186 (1981), which is hereby incorporated herein by reference.

oo 0 In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo for example by enzymatic hydrolysis, to release the biologically active parent. T.

Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.

Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference.

Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are Cl 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- WO 99/06397 PCTIUS98/15479 00 (propionyloxy)-1 -ethyl, 1-(pivaloyloxyl)-1 -ethyl, 1-methyl-lcI (propionyloxy)-1 -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, c- 5 cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the 00 like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1c 10 methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as 00 methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy-1 -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.

The term "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-ch lorobenzyloxycarbonyl, WO 99/06397 _19- PCT/US98/15479 0O9/6901- CIS8I57 0 0 p-methoxybe nzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-n itro-4,5-d imet hoxybe nzylIoxycarbo nyl1, 3,4,5trimethoxybenzyloxycarbonyl, 00 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, N- 10 ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 00 0 2,2,2,-trichioroethoxycarbonyl, phenoxycarbonyl, 0 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenyithiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "alkanoyl" 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 43 is an alkanoyl group and R 44 is an alkylene group.

The term "alkanoyloxyalkyl" as used herein refers to R 30

-O-R

31 wherein R 30 is an alkanoyl group and R 31 is an alkylene group. Examples of 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.

WO 99/06397 20- PCT/US98/15479 00 O The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon Satoms and also containing at least one carbon-carbon double bond.

Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH 3 CH2CH=CHCH 2 and the like.

The term "alkenyloxy" as used herein refers to an alkenyl group, as oo previously defined, connected to the parent molecular moiety through an oxygen linkage. Examples of alkenyloxy include allyloxy, Sbutenyloxy and the like.

N 10 The term "alkoxy" as used herein refers to R 4 1 0- wherein R 4 1 is a 00 0 loweralkyl group, as defined herein. Examples of alkoxy include, but are l not limited to, ethoxy, tert-butoxy, and the like.

The term "alkoxyalkoxy" as used herein refers to R 80 0-R 8 1 0wherein R 80 is loweralkyl as defined above and R 8 1 is alkylene.

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

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

Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.

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

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

The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety 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(0)-R 3 5 wherein R 3 4 is an alkoxy group and R 35 is an alkylene group. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, methoxcarbonylethyl, ethoxycarbonylmethyl and the like.

-21- WO 99/06397 PCT/S98/15479 00 O The term "alkoxycarbonylaminoalkyl" as used herein refers to cl R 38

-C(O)-NH-R

3 9 wherein R 38 is an alkoxy group and R 39 is an alkylene group.

g The term "alkoxycarbonyloxyalkyl" as used herein refers to s R 36 -C(0)-O-R 37 wherein R 36 is an alkoxy group and R 37 is an alkylene group.

00oo The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy Sradical. Examples of (alkoxycarbonyl)thioalkoxy include N 10 methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.

00 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 including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

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

The term "alkylamino" as used herein refers to R 51 NH- wherein

R

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

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

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- WO 99/06397 PCT/US98/15479 00 The term "alkylaminocarbonylaminoalkyl" as used herein refers to C R 4 0-C(O)-NH-R 4 1 wherein R 4 0 is an alkylamino group and R 4 1 is an alkylene group.

C 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 0o -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 SR88S(0)2NHR89- wherein R88 is loweralkyl and R89 is alkylene.

N 10 The term "alkylsulfonylamino" as used herein refers to an alkyl oo 0 group as previously defined appended to the parent molecular moiety Sthrough a sulfonylamino 2 group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include H-C=C-CH 2

H-C-C-CH(CH

3 and the like.

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

-C=C-CH(CH

3 and the like.

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

The term "aminocarbonyl" as used herein refers to 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.

WO 99/06397 -23- PCTIUS98/5479 00 O The term "trialkylaminoalkyl" as used herein refers to CN (R90)(R91)(R92)N(R93)- wherein R90, R91, and R92 are independently selected from loweralkyl and R93 is alkylene.

The term "aroyloxyalkyl" as used herein refers to R 32

-C(O)-O-R

33 C s wherein R 32 is an aryl group and RS 33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.

00oo 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 i 10 and the like. Aryl groups can be unsubstituted or substituted with one, 00 two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, trialkylaminoalkyl, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy, hydroxalkoxy, phenyl and tetrazolylalkoxy. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "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 42 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 45 0- wherein R 45 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

62 C(0)O- wherein R 62 is an arylalkyl group).

WO 99/06397 -24- PCT/US98/15479 00 0 The term "aryloxyalkyl" refers to an aryloxy group as previously Sdefined 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 5 radical, -C(O)H.

The term "carboxy" as used herein refers to a carboxylic acid oo 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 l 10 defined. Examples of carboxyalkenyl include 2-carboxyethenyl, 3- 00 0 carboxy-1-ethenyl and the like.

SThe term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.

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

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

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

R

6 0 wherein R 60 is a cycloalkyl group).

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

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 R5 6

R

57

N-

wherein R 5 6 and R 5 7 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.

WO 99/06397 -25- PCT/US98/15479 00 0 The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.

SThe 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, oo diethylaminocarbonyl and the like.

The term "dialkylaminocarbonylalkenyl" as used herein refers to San alkenyl radical to which is appended a dialkylaminocarbonyl group.

N 10 The term "dialkylaminocarbonylalkyl" as used herein refers to 00 0 Rso-C(0)-R 5 1 wherein R 5 0 is a dialkylamino group and R 5 1 is an alkylene group.

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

The term "haloalkenyl" as used herein refers to an alkenyl radical to which 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 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 9r%- WO 99/06397 PCTIUS98/1 5479 00 another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, Cl 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, 00 piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, N- 10 isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, 00 benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.

Heterocyclics also include compounds of the formula C where X* is -CH 2 or and Y* is or where R" is hydrogen or Cli-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.

Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, aminoalkyl, trialkylaminoalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO 3

H,

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- WO 99/06397 PCT/US98/15479 00 0The term "heterocycliccarbonyloxyalkyl" as used herein refers to

R

46

-C(O)-O-R

47 wherein R 4 6 is a heterocyclic group and R 4 7 is an alkylene group.

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

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

oo The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4- N 10 hydroxybutoxy and the like.

oo 0 The term "hydroxyalkyl" as used herein refers to a loweralkyl 0 radical to which is appended a hydroxy group.

The term "leaving group" as used herein refers to a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, 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 formation of a benzodioxolyl radical. o. Ethylenedioxy substituted on a phenyl ring results in the formation of a benzodioxanyl 0 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 N- N or a tautomer thereof.

-28- WO 99/06397 PCT/US98/15479 00 The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl Sradical as defined above appended to an alkoxy group as defined above.

Examples of tetrazolylalkoxy include tetrazolylmethoxy, 2 tetrazolylethoxy and the like.

N 5 The term "thioalkoxy" as used herein refers to R70S- wherein R 7 0 is loweralkyl. Examples of thioalkoxy include, but are not limited to, oo methylthio, ethylthio and the like.

The term "thioalkoxyalkoxy" as used herein refers to R80S-R 8 1 0- Swherein

R

80 is loweralkyl as defined above and R 8 1 is alkylene.

Representative examples of alkoxyalkoxy groups include CH 3

SCH

2 0-, 0 EtSCHgO-, t-BuSCHgO- and the like.

0 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

CH

2

OCH

2

CH-,

CH

3 SCH20CH 2 and the like.

The term "trans,trans" as used herein refers to the orientation of substituents (R 1 and R 2 relative to the central substituent R as shown R2 1Z N R 3

I

(CH

2 n R1 The term "trans,cis" as used herein refers to the orientation of substituents (Ri and R 2 relative to the central substituent R as shown

R

2 ZN R 3 R ZN R 3 N

N

(CH

2 R (CH2)nR (CH2) 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 WO 99/06397 -29- PCT/US98/15479 c-i N X(-CH2 )n 00 Preferred compounds of the invention are selected from the group consisting of: 5 trans-trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 00propyl-N- n-pentanesuIfo nylamino) pro pyl]-pyrrolidi ne-3 carboxylic acid; c-i trans, trans-2-(4-Methoxymethoxyphenyl)-4-(1 2 -(N-propylI-N- n-pentanesuIf onylami no) ethyl]pyrro lid i ne-3carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol 5 -yI)-1 (N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3.

carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 (N-propyl-N-n-hexane suItonylam ino)ethyl]py rro idi ne-3carboxylic acid; trans, trans-2- (4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 propyl-N-n-pentanesulfonylamino)ethyt]pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Dif luorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1

N-

di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(3,4-Difluorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3.carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1,3-benzodioxoI5-yi)- 1 -[2-(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluo ro-4-methoxypheny)4.(1 1 -(2-(N-propyl-N-(3-chloropropanesulfonyl)amino)ethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4.(1 1 -(2-(N-isobutyl-N-(3chloropropanesulfonyl)amino)ethyl)pyrrolidine-3carboxylic acid; Iqn- WO 99/06397 rPiiUy 5ii 4 00 trans, trans-2-(3-FlIuoro-4-methoxypheny1) ben zodioxolI-5-y I) 1-[2-(N-propyl-N-(4methylbutanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxy-3-fluorophenyI)-4-(7-methoxy-1 13benzodioxol-5-yI)-1-[2-(N-propyl-N-(npentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; 00 trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(2,2,3,3,3-pentafluoropropoxyethanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; Nl 10 trans, trans-2-(1 1 4-Benzodioxan-6-yI)-4-(7-methoxy-1 ,3-benzodioxol- 00 0 5-yI)-1-[2-(N-propyi-N-(n- 0 pentanesulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1-(2-(N-(2-methoxyethyl)-N- (pentanesulfonyl)amino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -12-(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphelyl)-4-(1 1 1 -(2-(N-(2-methoxyethyl)-N-(butanesulfonylamino)ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2- Flu oro-4- met hoxyp heny1) (1 ,3-be nzod yI)-1 -[2-(N-propyl-N-(2methylpropanesulfonyl)amino.)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxypheny)-4-(1 1 (2-(N-isobutyl-N-(b utan es uIf onylam ino)) ethyl) py rrol idine-3carboxylic acid; trans, trans-2-(2-Methylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 -(N,N-di(nbutyl)aminocarbonyimethyl)-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; -141- WO 99/06397 PC/S8/57 00 trans, trans-2-(2-(1 .3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1ci(N, N-di (n-butyI) am inocarbonyl met hyl)-py rro Iid in e.3-carboxy Iic acid: trans, trans-2-(2-(2-Tetrahydro-2H-pyran)ethy1) 4-(1 benzodioxol- N- 5 5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3 carboxylic acid; 00 trans, trans-2-(2,2,4-Trimethyl-3-pentenyl)-4(1 1 iN-di(n-butyI)aminocarbonylmethyl)-pyrroidine3carboxylic acid; 00 benzodioxol-5-yI)-1 -(NN-di(n-butyI)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yJ)-1 [[N-4-heptyl-N(2 methyl-3-fluorophenyl)] amino carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 1 3 -Dioxol-2-yI)ethyl)-4-(7-methoxy-1 13benzodioxol-5-yI)-1 -(N,N-di(n-butyI)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)..methyl)4-(1,3-benzodioxol-5-yI)- 1 -(N,N-di(n-butyI)aminocarbonylmethyl)-pyrroidine3carboxylic 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-Oxopyrrolidin- 1-yl)ethyl)-4(1 yI)-1 -(N,N-di(n-butyI)aminocarbonylmethyl)-pyrrohidine-3carboxylic acid; trans, trans-2-(2-(1 1 3-Dioxol-2-yl)ethyl)-4-(7-methoxy.1 3- 1 -(N-4-heptyt-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)4(7-methoxyl yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-( 2 2dimethypenty)4(23dihydrobenzof 1 -(NN-di(n-butyl)aminocarbonylmethyl)pyrrolidine3carboxylic acid; -32- WO 99/06397 PCTIUS98/15479 00 trans, trans-2-(2,2,-Di met hyl-2-(1 ,3-dioxolIan -2-y I) ethy1) methoxy-1 ,3-benzodioxol-5-yI)-1 -(N,N-di(nbutyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(1 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; 00 trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; N' 10 trans, trans-2-(2-(2-pyridyl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 00 0 di(n-butyI)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yl)ethyl)-4-(1 yI)-1 -(N-4-heptyl-N-(4-fluoro-3meth ylphe nyl))amni nocarbo nylm ethyl) -py rro lidi ne-3-carboxyl ic acid; trans, trans-2- 1 -py razo ly1) ethyl) (1 ,3-be nzod ioxol1-5-yI)- 1 Ndi(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 -E(Nbutyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; (2R,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)-1 -(N-4-heptyl-N-(4-fluoro-3meth ylphe nyl)) am inocarbo nyl methyl) -py rro lid ine-3-ca rboxyl ic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 yI)-1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; 7.

WO 99/06397 -33 PCTIUS98/15479 00 trans, trans-2-(2,2-DimethylIpen t-3-eny1)-4-(1 ben zodioxol-5-y1) -1 Cl(N- 4 -heptyl-N-(4-f Iuo ro-3-methylpheny am ino carbo ny Imet hy I) pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4(1 1 3-benzodioxol-5-yI)- 1 utyl-N- (4-d imet hylam ino)butyl) am inoca rbo nyl methyl)pyrrolidine-3-carboxylic acid; 00 trans, trans-2-(2,2-Dimethylpent-3-enyl)-4.(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(n-butyI)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; N 1 trans, trans-2-(2,2-Dimethylpent-3-enyl)-4(7-methoxy.1 3- 00 benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2,2-Dimethylpent-3-enyl)-4(7-methoxy-1,3benzodioxol-5-yI)-1 -((N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl)pyrroldine-3.

carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3enyl)-4(1 1 -(N-4-heptyl-N-(4-fluoro-3- !0 ~methylphenyl))aminocarbonylmethyl)pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3-enyl)-4-(1 1 -((N-butyl-N-(4-dimethylamino)butyl)aminocarbonymethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent-3enyI)-4(7.methoxy-1,3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2 1 4-Trimethylpent-3-enyl)-4-(7-methoxyl ,3- 1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbo nylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2,4-Trimethylpent3eny)4(7..methoxy1 13be nzodioxol-5-yI)-1 -((N-butyl-N-(4dimethylamino)butyl)aminocarbonylmethyl)pyrrolidine-3carboxylic acid; -34- WO 99/06397 PCTIUS98/15479 00 trans, trans-2-(2-(1 ,3-DioxoI-2-y I) ethy1) ben zodioxol-5-y1) -1 [(N-butyl-N-(4-dimethylam inobutyI) am ino) carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 1 3-Dioxol-2-y)ethyl)-4-(7-methoxy-1 33benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3.

00 carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yI)ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3- N- 10 methylphenyl))aminocarbonylmethyl).pyrrolidine-3..carboxylic 00 0 acid; 0 trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 33benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)am ino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-Dioxol-2-yI)ethy;)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))aminocarbonylmethyl).pyrrolidine.3-.carboxylic acid; trans, trans-2-(2,2-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl].pyrrolidine.3 carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-( 1,3-benzodioxol-5-yI)- 1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrrolidine.3.carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)4(1 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxypheny)ethy)4(7-methoxy-1,3benzodioxol-5-yi)-1 (NN-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxypheny)ethy)4(7-methoxy-1 3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3methylphenyl))ami no)carbonylmethyl]-pyrrolidine-3-.carboxylic acid; WO 99/06397 -35- PCT/US98/15479 00 trans, trans-2-(2-(2-MethoxyphenyI) -ethyI) -4-(7-methcxy-1,3benzodioxol-5-yi)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-( 1,3-benzodioxol-5-yI)- 1 -(N-4-heptyl-N-(4-fluoro-3- 00 methylphenyl))amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(1 N- 10 1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

00 0 pyrrolidine-3-carboxylic acid; 0 ~trans, trans-2-((2-Methoxyphenoxy)-methyI)-4-(7-methoxy-1,3benzodioxol-5-yI)-1- (N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4-(7-methoxyl ,3benzodioxol-5-yI)-l1-(N-4-heptyl-N-(4-fluoro-3methylphenyl))amino)carbonylmethyl]-pyrroldine-3-.carboxylic acid; trans, trans-2-(2-(2-Methoxyphenoxy)-methyl)-4-(7-methoxy-1 ,3benzodioxol-5-yt)-1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxo 1 ,2-dihydro pyridin-1 -yI)-ethyl)-4-(1 ,3benzodioxol-5-yI)-1 N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(1 yI)-1 -[(N-4-heptyl-N-(4-fiuoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yI)-ethyl)-4-(1 yI)-1 -[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyridin-1 -yl)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-l1-(N,N-di(N-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2- (2-Oxopy rid in- 1 -y1) -ethyl1)-4- (7-methoxy-1, ,3benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-flIuoro-3- WO 99/06397 -36- PCT/US98/15479 00 m ethylIph eny1) am ino) carbonyl met hy]pyrro Iid ine-3ca rboxy Iic acid; trans, trans-2-(2-(2-Oxopy rid in-1 -y I) -ethyl)-4-(7-methoxy-1 23ben zodioxol-5-y I) 1-[(N-butyI N-(4d imeth ylIam ino butyI) am ino) carbon y Ime thy Q-pyrro Iid ine-3 carboxylic acid; 00 trans, trans-2-(2(-2-Oxopiperidin-1 -yI)-ethyl)-4-(1 yI)-1 -(N,N-di(N-butyl)aminocarbonylmethyl)-pyrrolidine.3carboxylic acid; Nl 10 trans, trans-2-(2-(2-Oxopiperidin-1-y)ethy)-4(1 00 0 yI)-l-[(N-4-heptyl-N-(4-fluoro-3 0 methylphenyl)amino)carbonylmethyl]pyrrolidine-3carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-I. -yI)-ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(N-butyl)aminocarbonylmethyl).

pyrroiidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin-1 -yI)-ethyl)-4-(7-methoxy-1 23benzodioxol-5-yI)-l1-(N 2 N-di(N-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopiperidinl1 -yI)-ethyl)-4-(7-methoxy-1 23benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluo ro-3methylphenyI)amino)carbonylmethy]-pyrroidine-3.carboxylic acid; trans, trans-2-(2-(2-Oxopiperidin.1 -yI)-ethyl)-4-(7-methoxy-1 13benzodioxol-5-yI)-l -[(N-buty-N-(4dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(propoxy)amino)carbonylmethyl]..pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidinl1 -yt)ethyl)-4-(1 yI)-1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; -027 WO 99/06397 -U-PCT/US98/I 5479 00 trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 c-I y1)-1 -[(N-butyl-N-(4trimet hylIam mon iob utyI)a min o)carbo ny Imethyl..py rro idi ne.3 carboxylic acid; trans, trans-2-(2-(2-Qxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -(N,N-di(N-butyl)aminocarbonylmethyl).

00 pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-butyl-N-(3- N 10 hydroxypropyl)amino)carbonylmethyl].pyrrolidine.3.carboxylic 00 acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3- 1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethy]-pyrrolidine.3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 33benzodioxol-5-yl)-1 utyl-N- (propoxy)amino)carbonylmethyl]-pyrrolidne3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yl)-1 -[(N-butyl-N-(4d imethyl am inob utyI) amino) carbon ylm ethyl] -p yr rolid in e-3carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(7-methoxy-1 ,3benzodioxol-5-yi)-1 -[(N-butyl-N-(4trimethylammoniobutyl)amino)carbonylmethyl]pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-yl)-1 -(NN-di(N-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yl)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methy lphe nyl) am ino) carbo nyl methyl]- pyrro lid ine.3-ca rboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(2,3-dihydrobenzofuran-5-yI)-1 -[(N-butyl-N-(4d imethylaminobutyl)ami no)carbonylmethy]-pyrroidine.3carboxylic acid; -38- WO 99/06397 PCT/US98/15479 0O9/6903- C/S8157 0 0 trans, trans-2-(2-(3,3-Dimethyl-2oxopyrrolidin-1 -yI)ethyl)-4-(1 ,3benzodioxol-5-yi)-1 -(NN-di(N-butyl)aminocarbonylmethyl)yrrolidine-3-carboxylic acid; trans, trans- 2- D imethy -2-oxopy rro id in 1 -yI) ethyl)-4-(1 ,3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl-pyrrolidine.3-.carboxylic 00 acid; trans, trans-2- D imethy -2oxopy rroi~d in -1 -yI) ethyl1)-4-(1 ,3 benzodioxol-5-yI)-l-[(N-butyIN-(4- Cl 10 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3 00 0 carboxylic acid; 0 ~trans, trans-2-(2-(4,4-Dimethyl-2oxopyrrolidin..1 -yI)ethyl)-4-(1 ,3benzodioxol-5-yI)-l1-(N,N-di(N-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; transtrans-2-(2-(4,4-Dimethy-2oxopyrroidin-1 -yl)ethyl)-4-(1 ,3benzodioxol-5-yI)-l1-[(N-4-heptyl-N-(4-fluo ro-3methylIphe nyl) amin o) carbo nlmethyl].pyrro lid ine-.3..carboxy Iic acid; trans, trans-2-(2-(4,4-Dimethyl-2-oxopyrroidin.1 -yl)ethyl)-4-(1 ,3benzodioxol-5-yl)-l-[(N-butyl-N-(4.

dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4(1 1 N-dibutylaminocarbonylmethyl)-pyrrolidine-3-.carboxylic acid; trans, trans-2-(2-(1 -propanesultamyt)ethyl)-4-(1 1 1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl].pyrrolidine.3.carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1-[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1 -[(N-butyl-N-(propoxy)amino)carbonylmethyllpyrrolidine-3carboxylic acid; WO 99/06397 -39- PCT/US98/15479 00 trans, trans-2-(2-(1 -propanesultamyl)ethyl)-4-(1 1-[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 -propanesultamyI)ethyI)-4-(7-methoxy. 1,3benzodioxol-5-yI)-1 -(NN-di(n-butyI)aminocarbonylmethy).

pyrrolidine-3-carboxylic acid; 00 trans, trans-2-(2-(1 -propanesultamyI)ethyI)-4-(7-methoxy-1 ,3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylpheny)amino)carbonylmethyl]-pyrrolidine-3carboxylic Ni 10 acid; 00 0 ~trans, trans-2-(2-(1 -PropanesultamyI)ethyI)-4-(7methoxy-1 3- 0 benzodioxol-5-yI)-l -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyll..pyrrolidine-3 carboxylic acid; trans, trans-2-(2- (1 -pro panes uItamyI)ethy)4(2,3-d ihydrobenzofuran-5-yI)-1 -(NN-di(n-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -propanesultamyl)ethyl)-4-(2,3-dihydro- 1 -[(N-4-heptyl-N-(4-fluoro-3m ethy Iphe nyl)am in o)carbo nyl methyl]pyrroli~d ine-3carboxyl ic acid; trans, trans-2-(2-( 1 -propanesultamy)ethyl)4(2,3dihydro- 1 -[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl-pyrrolidine.3 carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yI)-1 4 -heptyl-N-( 4 -fluoro-3-methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 -pyrazolyl)ethyl)-4-( 1,3-benzodioxol-5-yI)-1 butyl-N-( 3 -hydroxypropyl)amino)carbonylmethyl]pyrrolidine-3 carboxylic acid; trans, trans-2- -pyrazo lyl) ethyl) ,3-be nzodioxol1-5-yI)- 1 butyl-N-(propoxy)amino)carbonylmethyl]-.pyrrolidine-.3-carboxylic acid; trans, trans-2- -py razo ly1) ethyl) ,3-be nzodioxo 1-5-yI1)- 1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; WO 99/06397 -40- PCT/US98/15479 00 trans, trans-2-(2-( 1 -pyrazo I yI)ethy1) met hoxy 1 ben zodioxolI- -yl)-1 -(N,N-dibutylaminocarbonylmethyl).pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 -py razolyl) ethyl) -4-(7-methoxy- 1,3-be nzodioxol- 5-yl)-1-[(N-4-heptyl-N-(4-fluoro-3methy lphe nyl) am ino) carbo nyl methy ].pyrro lid ine.3carboxylIi c 00 acid; trans, trans- 2- (1 -pyrazolyl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol- 5-yl)- 1-[(N-butyl-N-(4- 0 0 carboxylic acid; c-itrans, trans-2-(2-(1 -pyrazolyI)ethyI)-4-(2,3-dihydro-benzofuran-5y).

1 N-dib utylam inocarbonylImethyI)-pyrrolid in e-3ca rboxylic acid; trans, trans-2-(2-( 1 -py razoly I)ethyl1)-4- (2,3-d ihyd ro-benzof uran 5-y) 1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-.pyrrolidine..3.carboxylic acid; trans, trans-2-(2-(1 -pyrazolyl)ethyI)-4-(2,3-dihydro-benzofuran-5yi).

1 -[(N-butyl-N-(4-dimethylaminobutyl)ammno)carbonylmethyl]pyrrolidine-3-carboxylic acid; transtrans-2-(2-(2-oxazoly)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; trans, trans-2- (2-(Oxazo-2-y) ethyl) (1 ,3-be nzodioxol1-5-yl1) -1 (N- 4 -heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(Oxazof-2-yI)ethyl)-4(1 ,3-benzodioxol-5-yI)-1 but yl -N h ydro xy prop yI)amino) carbon yl methyl] -p yr rolid in e-3carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(propoxy)amino)carbonylmethyl..pyrrol idine-3-carboxylic acid; trans, trans-2-(2-(Oxazol-2-yl)ethyl)-4(1 ,3-benzodioxol-5-yl)-1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl].

pyrrolidine-3-carboxylic acid; WO 99/06397 -41- PCT/US98/15479 0O9/697-1 C/U9/57 0 0 trans, trans-2-(2-(Oxazol-2-y I) ethyI) -4-(7-methoxyl 1,3-benzodioxolI- 5-y1) -1 -(N,N-di(n-butyI) am inocarbony Imet hy pyrro Iidine-3 carboxylic acid; trans, trans-2-(2-(OxazoI-2-yI)ethyl)-4-(7-methoxy 1 ,3-benzodioxol- 5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl].pyrrolidine-3..carboxylic 00 acid; trans, trans-2-(2-(Oxazo-2-y)ethyl)-4-(7-methoxy-1 ,3-benzodioxol- 5-yI)-1-[(N-butyl-N-(4- 0I dimethylaminobutyl)amino)carbonylmethyllpyrrolidine-3 00 0 carboxylic acid; citrans, trans-2-(2- (5-M ethyl oxazo 1-2-y) eth 1,3-be yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyly..pyrrolidine-3 carboxylic acid; trans, trans-2- (5-M ethyl oxazol1-2-yi) ethy)4-( 1,3-be nzod yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl].pyrrolidine-.3..carboxylic acid; trans, trans-2- (5-M ethyl oxazo 1-2-yI) ethy)4-( 1,3-be nzod .T yi)-l-[(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- Dioxopyrro lid in -1 -y1) ethyl)-4- (1 ,3-benzodioxol- 5-yI)-1 N-d i(n-b uty1) am inocarbo nyl methyl)-pyrro lid ine-3carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin. 1 -yI)ethyl)-4-(1 ,3-benzodioxol- 5-yI)-l1-[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl].pyrrolidine-3..carboxylic acid; trans, trans-2-(2-(2,5- Dioxopyrro lidinl -y1) ethyl) (1 ,3-benzod ioxolI- 5-yI)-1 -[(N-butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; trans, trans-2- Dioxo pyrro lid in-l -y1) ethyl)-4- (1 ,3-benzod ioxolI- 5-yI)-1 -[(N-butylI-N-(propoxy) am ino) ca rbo nylmethyl].pyrro lid ine.

3-carboxylic acid; trans, trans-2-(2- Dioxo py rro lid in-l -y1) ethyl) (1 ,3-be nzod ioxolI- -yI)-1 -[(N-butyl-N-(4-dimethylaminobutyl) amino)carbonylmethyI]-pyrrolidine-3-carboxylic acid; -42- WO 99/06397 -42- PCT[US98/1 5479 00 trans, trans-2-(2-(2,5-Dioxopyrroidin-1 -yI) ethy1) me thoxy-1 3benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2,5-Dioxopyrrolidin-1 -y)ethy)4(7-methoxy-1 3benzodioxol-5-yI)-1 -[(N-4-heptyl-N-(4-fluoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3-.carboxylic 00 acid; trans, trans-2- (2-(Py rid in-2-y) ethy (1,3-be nzod ioxol1-5-yI)- 1 4 -heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl].

N 10 pyrrolidine-3-carboxylic acid; 00 trans, trans-2-(2-(Pyridin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yI)-1 butyl-N-(3-hydroxypropyl)amino)carbonylmethyl]-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4-(1 ,3-benzodioxoi-5-yI)-1 butyl-N-(propoxy)amino)carbonylmethyl]pyrrolidine3carboxylic acid; trans, trans-2- (Py rid in ethyI)-4-(1 ,3-be nzod ioxo 1-5-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- 1 N-d i(n-b utyl) am inocarbo nyl met hyl)-pyrro Iid ine-3 carboxylic acid; trans, trans-2-(2-(Pyridin-2-yl)ethyl)-4-(7-methoxy-1 ,3-benzodioxol- -yI)-l1-[(N-4-heptyl-N-(4-fI uoro-3methylphenyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic acid; trans, trans-2-(2-(Pyridin-2-yI)ethyl)-4-(7-methoxy-1,3-benzodioxol- 5-yI)-l1-[(N-butyl-N-(4dimethylaminobutyl)amino)carbonylmethyl].pyrrolidine.3 carboxylic acid; trans, trans-2- (2-(Py rim idi n-2-yI) ethyl)-4-(1 be nzod ioxol1-5-yI)- 1 (N ,N-di(n-butyI)aminocarbonylmethyI)-pyrrolidine-3..carboxylic acid; trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yi)-1 4 -heptyl-N-(4-fluoro-3-methylphenyl)amino)carbonylmethyl]pyrrolidine-3-carboxylic acid; WO 99/06397 -43- PCT/US98/15479 00 trans, trans-2-(2-(Pyrimidin-2-yl)ethyl)-4(1 ,3-benzodioxol-5-yl)-1- [(N-butyl-N- (4-di methylIam inobutyl)am ino) carbo nyl methyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(2-( 1 3-benzodioxol-4-yl)ethyl)-4-(1 yI)-1 -(NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; 00 trans, trans-2-(2-(1 ,3-benzodioxol-4-yl)ethyl)-4-(1 ,3-benzodioxol- yl)-1-[(N-4-heptyl-N-(4-fluoro-3 methylphenyl)amino)carbonylmethyl]-pyrrolidine-3carboxylic N- 0 acid; and 00 0 trans, trans-2-(2-( 1 3-benzodioxol-4-yl)ethyl)-4-(1 yl)-1 -[(N-butyl-N-(4 dimethylaminobutyl)amino)carbonylmethyl]pyrrolidine-3-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 1 -(NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; 2

S,

3 R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl)..4.(7-methoxy-1,3- 0 benzodioxol-5-yl)-1 -(NN-di(n-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-((2-Methoxyphenoxy)-methyl)-4(1 1 -(NN-di(n-butyl)aminocarbonylmethyly..pyrrolidine-3-carboxylic acid; (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl).4-(1 ,3-benzodioxol-5-yl)-1 (N ,N-di(n-butyI)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 3-Dioxol-2-yl)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 ,N-d i (n-b utyl)a min ocarbonyImethyl).pyrro lid in e-.3.carboxyl ic acid; WO 99/06397 -44- PCT/U598/15479 00 trans, trans-2-(2,2,- Di met hyl-2(1 ,3-dioxolIan -2-y I) ethy1) ,3ci benzodioxol-5-yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(1 ,3-Dioxol-2-y I)ethy!)-4- (1 ci 5 -1l-[[N-4-heptyl-N-(2-methyl-3-fluorophenyl)] aminocarbonylmethyl]-pyrrolidine3carboxylic acid; 00 trans, trans-2-(2- (1, 1 3 Dioxo ethyl) meth oxyl 1,3benzodioxol-5-yI)-l -(N,N-di(n-butyl)aminocarbonylmethyl).

pyrrolidine-3-carboxylic acid; trans, trans-2-((2-Methoxyphenoxy)-methyl)-4(1 00 0 1l-(NN-di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic 0 acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; trans, trans-2-(2-(1 1 3 -Dioxol-2-y)ethyl)-4-(7-methoxyl ,3benzodioxol-5-yI)-1 -(N-4-heptyl-N-(4-fluoro-3meth yIp he nyl))am inoca rbonyl methy I)py rro lid ine-3-carboxy ic acid; trans, trans-2-(2,2-Dimethylpentyl)-4(7-methoxy.1 yI)-l1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3carboxylic acid; trans, trans-2-(2,2,-Dimethy-2-(l ,3-dioxolan-2-yl)ethyl)-4-(7methoxy-1 ,3-benzodioxol-5-yI)-1 -(N,N-di(nbutyI)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl).4-(1 1 N-di(n-butyl)aminocarbonylmethyl).pyrrolidine3carboxylic acid; trans, trans-2-(2,2-Dimethyl3(E)pentenyl)4(7-methoxyl ,3benzodioxol-5-yI)-1 -(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; (2S, 3R, 4S) -2-(2-(2-oxopy rro lid in- 1 -yI)ethyl)-4-(1 ,3-be nzodioxo yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 -45- PCT/US98/15479 00 (2S, 3R, 4S)-2-(2,2 Dimethylpentyl)-4-(7-methoxy.1 y)-l -(NN-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).pyrroidine-.3..carboxylic 00 acid; trans, trans-2-(2-(1 -pyrazolyl)ethyl)-4(1 ,3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3-carboxylic acid; Nl 10 (2 R, 3R, 4 S)-2-(3-Fluoro-4-methoxyphenyl)-4(1 00 0 1 -[((N-propyl-N-pentanesulfonyl)amino)ethyl]-pyrrolidine-3 0 carboxylic acid; (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 3 3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethyl)pyrrolidine-3carboxyic acid; 1 -(NN-di(n-butyl)aminocarbonylm ethyl) -py rroidi ne3carboxyl ic acid; 2

S,

3

R,

4 S)-2-(2,2-Dimethylpent(E)3enyl)4(7-methoxy-1,3benzodioxol-5-yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)..

pyrrolidine-3-carboxylic acid; 2 S,3R,4S)-2-((2-Methoxyphenoxy)-methyl).4(1 1 -(NN-di(n-butyl)aminocarbonylmethyl>.pyrrolidine3carboxylic acid; and 2 S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl).4-(1 .3-benzodioxol-5-yl)-1 (NN-di(n-butyl)aminocarbonylmethyl).pyrrolidine3carboxylic 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 WO 99/06397 -46- PCT/US98/15479 00

O

0 -C02H. A P-ketoester 1, where E is loweralkyl or a carboxy protecting group is reacted with a nitro vinyl compound 2, in the presence of a Sbase (for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or sodium ethoxide or sodium hydride and the like) in an inert solvent such as toluene, benzene, tetrahydrofuran or ethanol and the like. The condensation product a is reduced (for example, hydrogenation using a oo Raney nickel or platinum catalyst). The resulting amine cyclizes to give the dihydro pyrrole 4. Reduction of 4 (for example, sodium Scyanoborohydride or catalytic hydrogenation and the like) in a protic 10 solvent such as ethanol or methanol and the like gives the pyrrolidine 00 compound 5 as a mixture of cis-cis, trans,trans and cis,trans products.

ci Chromatographic separation removes the cis-cis isomer leaving a mixture of the trans,trans and cis,trans isomers which is further elaborated. The cis-cis isomer can be epimerized (for example, using sodium ethoxide in ethanol) to give the trans,trans isomer and then carried on as described below. The pyrrolidine nitrogen is acylated or sulfonylated with R 3 -X (R 3 is R 4 or R 6 -S(0) 2 and X is a leaving group such as a halide (Cl is preferred) or X taken together with

R

4 or R6-S(0) 2 forms an activated ester including esters or 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, Cl, Br or I) or X is a leaving group such as a sulfonate (for example, mesylate, tosylate, triflate and the like)) in the presence of a base such as diisopropyl ethylamine or triethylamine and the like to give the N-derivatized pyrrolidine 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 Z 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 -C0 2 H. A substituted benzyl chloride 9 is reacted with a lithio dithiane 10 in an inert solvent such as THF or dimethoxyethane to give the alkylated adduct 11. The anion of compound 11 is formed using a base such as n-butyllithium and then reacted with R 1

-CH

2 wherein X' is a WO 99/06397 -47- PCT/US98/15479 00 O leaving group such as a halide or sulfonate to give compound 12. The c dithiane protecting group is cleaved (for example, using a mercuric salt in water) to give the keto compound 1. Reaction of ketone J3 with i benzyl amine and formaldehyde gives the keto piperidine compound 14.

Treatment of compound 14 with an activated nitrile such as trimethylsilyl cyanide followed by a dehydrating agent such as oo phosphorous oxychloride provides the isomeric ene nitriles Reduction of the double bond (for example, using sodium borohydride) affords the piperidinyl nitrile 1.6. Hydrolysis of the nitrile using c 10 hydrochloric acid in the presence of a carboxy protecting reagent (for oo 0 example, an alkyl alcohol) affords ester 17 (where E is a carboxy S protecting group). Debenzylation by catalytic hydrogenation under acidic conditions affords the free piperidine compound 18. Compound 18 is further elaborated by the procedures described in Scheme I for compound 5 to give the final product compound 19.

Scheme III illustrates a general procedure for preparing the compounds of the invention when m and n are 0, Z is and W is

-CO

2 H. P-Keto ester 2U (wherein E is loweralkyl or a carboxy protecting group) is reacted with an ac-haloester 2J1 (where J is lower alkyl or a carboxy protecting group and the halogen is bromine, iodine or chlorine) in the presence of a base such as NaH or potassium tertbutoxide or lithium diisopropylamide in an inert solvent such as THF or 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 Cl). Compound 52 is treated with diazomethane to -48- WO 99/06397 PCT/US98/15479 00 0 give the diazo ketone 53. Rearrangement of compound 5 (for example, using water or an alcohol and silver oxide or silver benzoate and Striethylamine, 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.

oo 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 N 10 give compound 28. Catalytic hydrogenation using Raney nickel leads to Sreduction of the nitro group to an amine and subsequent cyclization to Sgive the dihydropyrrole 9. The double bond is reduced with sodium cyanoborohydride to give the pyrrolidine compound 30 as a mixture of cis-cis, trans,trans and cis,trans isomers. Chromatography separates out the cis-cis isomer, leaving a mixture of the trans,trans and cis,trans isomers (3J).

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

Scheme VII illustrates the preparation of a specific piperidinyl compound. Benzodioxolyl methyl chloride 5 is reacted with lithio dithiane 36 to give the alkylated compound 3Z. Treatment of compound 37 with 4-methoxybenzyl chloride in the presence of lithium diisopropylamide gives compound i8. Cleavage of the dithiane protecting group using a mercuric salt in aqueous solution gives ketone 9. Treatment of 3 with benzylamine and formaldehyde gives the keto piperidine 4Q. Treatment of compound 4Q 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 4. The N-benzyl protecting group is -4Q- WO 99/06397 PCT/US98/15479 00 removed by catalytic hydrogenation to give the free piperidine cI compound 44. Compound 44 is further elaborated by the procedures described in Scheme V for compound 21 resulting in the formation of 2 the N-derivatized carboxylic acid 3 s A preferred embodiment of the process shown in Scheme III is shown in Scheme VIII. 4-Methoxybenzoylacetate 46 (wherein E is oo loweralkyl or a carboxy protecting group) is reacted with an benzodioxolyl a-bromoacetate 47 (wherein E is lower alkyl or a carboxy protecting group) in the presence of NaH in THF to give diester 48.

c 10 Treating compound 48 with ethoxypropylamine and heating in acetic 00 acid gives the cyclic compound 49. The double bond is reduced by 0 catalytic hydrogenation using a palladium on carbon catalyst to give pyrrolidone 50. Epimerization with sodium ethoxide in ethanol to give the desired trans,trans configuration is followed by sodium hydroxide hydrolysis of the ester to afford the desired trans,trans carboxylic acid 51.

Scheme IX illustrates the preparation of compounds where n is 0, Z is -CH 2 and W is other than carboxylic acid. Compound 55, which 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 and triethylamine hydrochloride or trimethylsilylazide and tin oxide) is reacted to give tetrazole 58. Alternatively nitrile 7 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 1 WO 99/06397 50- PCT/US98/15479 00 O cyclization to compound 60. Alternatively reacting the amidoxime g c with thionyl chloride in an inert solvent (for example, chloroform, Sdichloromethane, dixoane and THF and the like) affords the Z oxathiadiazole 61.

5 Scheme X illustrates the preparation of compounds in which R3 is an acylmethylene group. A carboxylic acid 62 (where R 4 is as 00 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 o 10 chloride with excess ethereal diazomethane affords a diazoketone, and 0 then treatment with anhydrous HCI in dioxane gives the a-chloroketone 63. Pyrrolidine ester 5 where E is lower alkyl or a carboxy protecting group, prepared in Scheme I, is alkylated with the a-chloroketone 6 to provide alkylated pyrrolidine 64. Carboxy deprotection (for example, hydrolysis of an alkyl ester using lithium or sodium hydroxide in ethanol-water) gives the alkylated pyrrolidine acid Scheme XI illustrates the preparation of "reverse amides and sulfonamides". The carboxy protected pyrrolidine 5, prepared in Scheme I, is reacted with a difunctionalized compound

X-R

8 -X where R 8 is alkylene and X is a leaving group (for example a halide where Br is preferred) to give N-alkylated compound 6. Treatment of 6 with an amine (R20NH 2 affords secondary amine .67. This amine can be reacted with an activated acyl compound (for example, R 4 and then carboxy deprotected (for example, hydrolysis of an ester or hydrogenation of a benzyl moiety) to afford amide 68. Alternatively amine 67 can be reacted with an activated sulfonyl compound (for example, R 6 -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 Z2 Tsuge, S.

Kanemasa, K. Matsuda, Chem. Lett. 1131-4 (1983), 0. Tsuge, S.

Kanemasa, T. Yamada, K. Matsuda, J. Org. Chem. 52 2523-30 (1987), and S. Kanemasa, K. Skamoto, O. Tsuge, Bull. Chem. Soc. Jpn. 62 1960-68 (1989)). A specific example is also shown in Scheme XII. Silylimine 73 WO 99/06397 -51- PCT/US98/15479 00 O is reacted with acrylate 74 in the presence of trimethylsilyl triflate c and tetrabutylammonium fluoride to give the desired pyrrolidine 75 as a mixture of isomers. This method can be modified to provide the N- C acetamido derivatives directly by reacting Z and 4 with the appropriate bromoacetamide (for example, dibutyl bromoacetamide) in the presence of tetrabutylammonium iodide and cesium fluoride to give oo compound 76.

Scheme XIII illustrates a method for producing an enantiomerically pure pyrrolidine 80, which can be further elaborated Nc 10 on the pyrrolidine nitrogen. Intermediate racemic pyrrolidine ester Z 00 0 (for example, prepared by the procedure described in Scheme V) is Bocnitrogen protected (for example, by treatment with Boc 2 0) and then the ester is hydrolyzed (for example, using sodium or lithium hydroxide in ethanol and water) to give t-butyl carbamoyl pyrrolidine carboxylic acid 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 carboxylic acid Z9. 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, by treatment with the dibutyl amide of bromoacetamide in acetonitrile in the presence of diisopropylethylamine) to give optically active compound 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 55 is hydrogen or methyl) is condensed with a substituted acrylate 8i (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- WO 99/06397 PCT/US98/15479 00 O 5, 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 5 (88) is reacted with beta-keto ester J9 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine oo 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 No 10 temperature of from about 00 C to about 1000 C for a period of time 0 from about 15 minutes to ovemight to give compound 9q. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 9 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 on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine 91b.

The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, and the hydrogenation is continued to give pyrrolidine compound 22 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 93 is obtained by treatment of a mixture of the (+)-isomer and the (-)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid or -53- WO 99/06397 PCT/US98/15479 00 SD-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like.

The (+)-isomer of 9 selectively crystallizes as the salt, leaving the S(-)-isomer of 93 in solution. Alternatively, the substantially pure at least 95% of the desired isomer) optically active (-)-isomer of compound 93 can be selectively crystallized by reaction of a mixture of oo 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 cN 10 (+)-isomer of compound U in solution.

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

A more detailed description of the preparation of some specific analogs is provided in Schemes XVI-XXI. Aliphatic p-ketoesters (Scheme XVI) may be prepared by copper-catalyzed addition of a 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 -rA- WO 99/06397 PCT/US98/15479 00 catalyst. After removal of the Boc protecting group, for example with c TFA, the resultant amine is acylated, for example using bromoacetyl bromide.

SThe P-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 oo DBU or potassium t-butoxide; the resultant adduct is hydrogenated, for C example using Raney Nickel as catalyst, to give an imine, which is reduced further, for example using sodium cyanoborohydride under N 10 controlled pH. A mixture of isomers are generated, in which the trans- 0 trans is generally preferred.

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

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 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-(Qhydroxyalkyl)-N-alkyl haloacetamide. Hydrolysis of the resultant ester, for example using sodium hydroxide in aqueous alcohol, provides the product.

WO 99/06397 -55- PCT/US98/15479 00

O

0 For one particular class of electrophile, N-(n-hydroxyalkyl)-N- Salkyl haloacetamides, further transformations of the alkylation product E 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 oo dimethylamine, provides the corresponding amino ester, which may be hydrolyzed as previously described to provide product.

00

CIA

WO 99/06397 WO 9906397PCT/US9815479 -56- Scheme I 0 C0 2

E

R2 .At N02 C0 2

E

Mixture of Cis-Cis Trans-Trans Cis-Trans [H]j 2 C0 2

E

4 N R3

R

2 -I

-R

0O 2

E

Mixture of Trans-Trans Cis-Trans

(H

2 01 /R3 C0 2

H

Tranls-Tranls IR 3 C0 2

E

Cis-Trans WO 99/06397 WO 9906397PCT/US98/1 5479 -57- Scheme 11 R2,,,,Cl

LV#Q)

RI

0 14 O~N~C0 2

E

ISOMER

IfR2 WO 99/06397PCUS8147 PCT/US98/15479 -58- Scheme III Halo

R

2 f 0 21 0 J0 2 C R 2 Halo Cl, Br, or I 0

R

3

N

R

2 C0 2

E

N

C0 2

E

Trans-Trans WO 99/06397 WO 9906397PCT/US98/I 5479 -59- Scheme IV 00 00 60 2

H

0 L

CH

2

N

2 -p 3

R

2 -L R 1 N.C0 2

H

0 4%-HN 2 WO 99/06397 WO 9906397PCT/US98/1 5479 Scheme V C

H

3 0-0 EtO 2

C

B U 0 COOEt

CH

3 0 1 11% 0 2a

NO

2

AOO

H2I I0 C H 3 0

OK

COQEt 0 C F3 NaCNBH 3 Mixture of 32 Cis-Cis Travis-Trans hrmatographic separation Cis-Trans Cis-Cis Mixture of Trans-Trans and Cis-Trans WO 99/06397 WO 9906397PCT/US98/1 5479 -61- Scheme VI Cis-Trans .and BrCH 2

CONHCP

7 ob HiPr 2 NEt 0 CH 3 Trants-Trans 0010KN

HC

3

H

7 1=N 0 CH 3 COQEt Trans-Trans and Cis-Trans NaOH .H 2 0, EtOH Trans-TrantsCi-an Cis-Trans WO 99/06397 PTU9/57 PCT/US98/15479 -62- Scheme ViI 'DO, Cl

SQ

~ou OMe cm

N'

ISOMER

OMe e OMe WO 99/06397PCIS8147 PCT/US98/15479 00 -63- Scheme VII cont.

0 00 N

N

o oo, CN I~ OMe .ome 41 0" 0

I

H~ IONs 0N .C0 2 Et 44 OMe OMe OMe WO 99/06397 WO 9906397PCT/US98/15479 -64- Scheme VIII 2

E

,C0 2 r= 0- 0 1 o C H 3

'OCH

3 0 0 K 00 rl N/ 0

OCH

3 Trans-Trans WO 99106397 WO 9906397PCT/US98/I 5479 Scheme IX 00 00 /R 3 (CH2)m

(CH

2 )m NI N H

N=N

,R

3

(CH

2 )m

HN'~

0

(CH

2 )m1

CONH

2 R-QL R 1

(CH

2 )m

CON

,R

3

HN

%I

0

NOH

WO 99/06397 WO 9906397PCT/US98/I 5479 -66- Scheme X 00

R

4 y OH l0 0 -Il+ 0 0 R4 r N

C

2

H

0

R

2 R 4 N C 2

E

0

R

2 WO 99/06397 WO 9906397PCTIUS98II 5479 -67- Scheme XI

H

C0 2

E

0 R4 C0 2

H

C0 2

E

R

8

-NHR

20 C0 2

E

C0 2

H

WO 99/06397 WO 9906397PCT/US98/15479 1-68- Scheme X11 Rl

R

3 N+4

CH

2 C0 2 Et

R

2

R

1 R3,NjZ 7

C

2 Et Me3Si OCH3 0:0 C0 2 Et 0

OCH:

BU2N

%.N

0

PCH

3 'C0 2 Et WO 99/06397 WO 9906397PCTIUS98/I S479 00 00 00 -69- Scheme XI11 1. BOC 2 0 2. NaOH. EtOH

H

2 0

OCH

3 BocN -C0 2

H

2 W± M.f 1. (+)-cinchonine 2. recrystallize ironj EtOAc/hexane 3. Na 2

CO

3

HCI

HCI

EtOH (+)jQ 2 IBu 2

NC{O)CH

2 Br EtNiPr 2

CH

3

CN

OCH

3

CO

2 0 iC02H WO 99/06397PC/S/I57 PCTIUS98/15479 Scheme XIV 00 00

R

Ph N OMe Me 3

S."

H

2 Pd (OH) 2/C

R

3 Q -C0 2 R56 R2 'C0 2 R 6 EtOH, H 2 0

A

2

R

3 Br

BU

4 NI or Nal

CH

3

CN

R NQ

C

2

H

R

2 WO 99/06397 WO 9906397PCT/US98/1 5479 -71- Scheme XV R2 N0 2 0 0 O)

R

0 C0 2

E

R

2

R

C0 2

E

0 2 N 0 C0 2

E

C0 2

E

R

C0 2

H

NH

R

2

R,

C0 2

E

9 3

N

C0 2

E

WO 99/06397 WO 9906397PCTIUS98/1 5479 -72- SCHEME XVI COQEt nPrMgBr NaOH cat CuCI

HOO

CEt OEt NaOH N .heat OC CDI ca:OEt EtOOC CDI O~aOEt 0 EtOOC

I.

SCHEME XVII BocHN'0- I NaH

R-X

H2F 0 Pd-C 0 TFA BrCH 2 COBr BocN h 0 SCHEME XVIII 0 2 N O DBU O> 0 or cat. KOtBu

H

2 Ra-Ni NaBH 3

CN

HN .iCOOEt R 0 O WO 99/06397 WO 9906397PCTIUS98/1 5479 -73- SCHEME XIX

R

HN a .'COOEt (racemic) acid recrystaizatiofl neutralization HN giuCOOEt 0 (single enantiomer) (racemic) 1. EDAC, 2.FF 5 phenO6

R

91 -N'A 1. NaOMe, 1. BOC 2 0O 10 MeOH HN .aCOOMe 2. NaQH 3. separate 2. TFA diastereomers (single enantiomer) 1. EDAC, HOOB:

-N

1. BOC 2 0 1. HCI, heat HN a.COOEt 2. NaOH 3. separate 2. HCI, EtCH diastereomers/\ (racemic) (racmic)(single enanhiomer) WO 99/06397 WO 9906397PCTIUS98/1 5479 -74- SCHEME XX 0 R B

R

H N~

R

2 NaCH -"COOEt 0 &R 0 KI

COOH

1 2 1y.

SCHEME XXI 0 .11co~t BrN .,C00Et 2. LiBr 0 0 0 'R 0j (CH 3 2 NH F1 0- NaH 00 WO 99/06397 PCTIUS98/15479 Compounds which are useful as intermediates for the preparation of compounds of the invention are:

NH

(CH

2 n

(CH

2 )M C Iw (111) wherein n is 0 or 1; m is 0 to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protectinc -P0 3 1-2, -P(O)(OH)E where E is hydrogen, toweralkyl or aryla

-CN,

-C(O)NHR17 where R17 is loweralkyl, alkylaminocarboflyl, dial kylami nocarbonyl, tetrazolyt, hydroxy, alkoxy, sutfonamido, -C(O)NHS(O)2R16 where R 1 6 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) .S(O) 2 NHC(O)RI6.

HO 0 0 group, Ikyl, (0) WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -76- Ct OH

~N

(p) 000

(NH

0 00 Nq c-Ij 0 N C) S=O

H

Mt H or (u NS2F and

R

1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hiydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyatkoxyalkyt, cycloalkyt, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbOflylalkyl, aminocarbonylalkeflyl, alkylaminocarbonylalkeflyl, dialkytaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyi-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic) alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arlalkyl. 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; or a compound of the formula: WO 99/06397 PCTIUS98/15479 00 -77-

R

2 NH2

NH

ci

(CH

2 )n C (H)

__(CH

2 )m )M W Ror

W

00 (IV) (V Swherein n is 0 or 1; 00 m is 0toG6; C) W is -C(O) 2 -G where G is hydrogen or a carbj'xy protecting group, -P03H2, -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-ON,

-C(O)NHR17 where R17 is loweralkyl, alkylaminocarboflI dialkylaminoCarboflyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl6 where R16 is loweralkyl, haloalkyt, phenyl or dialkylamiflo, (in) -S(O) 2 NHC(O)R16,

HO

0

A

0 HO 0

OH

WO 99/06397 WO 9906397PCT/US98/1 5479 00 -78-

~NH

0, 00

NN

0 000 c-IA(s)

N

CZ

CF

3 Mt ~H or

NHSO

2

CF

3 (uM and R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hyd roxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl.

aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylami nocarbonyl alkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or aryIalkyl, 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 R1 and R 2 are as defined above; or the substantially pure or (+)isomer thereof.

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -79- Particularly preferred intermediates are compounds of formula S(Ill1), (IV) and wherein NI n and m are both 0; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; 00 and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, C* phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4- -i methoxyphenyl, 00 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4- Smethylphenyl, 4-trifluoromethylphenYl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-f Iuoro-4-ethoxypheflyl, 2-f luorophenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxaflyl or dihydrobenzofuralYl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-Nalkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1.3benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxaflyl, dihydrobenzofuranYl, benzofurnayl, 4-methoxyphenyl, dim ethoxyphenyl, 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:

R

2 N '-R5b

(CH

2 )n

(CH

2 )m w (V 1) WO 99/06397 WO 9906397PCT/US98/1 5479 00 00 wherein n is 0 or 1; m is 0 to 6; Rsb is alkylene; o is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3

H

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

-CN,

-C(O)NHRl7 where R1 7 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2Rl6 where R 16 is loweralkyl, haloalkyt, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6, HO 0

-NH

0

OH

'%N

0 0 WO 99/06397 WO 9906397PCT/US98/1 5479 00 -81-

N-

H 0 00 If S=0

N

Mt H ,or -a NHSO 2

CF

3 an R, and R 2 are independently selected from hydrogen. loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylamninocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkeflyl, alkyl amin ocarborlylalkell dialkylaminocarbolylalkell hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoy-N-alkyl)amiIoalkYI, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and RC is aklnwith the poiothat one or both of Rand

R

2 is other than hydrogen; or a salt thereof; or a compound of the formula: R2WeRsb Q R 2 N b

(CH

2 )n

CH)

(CH

2

(CH

2 )mC W R or W

R

(VI11) (Vill) wherein n is 0 or 1; m is 0 to 6; WO 99106397 WO 9906397PCTIUS98/15479 00 -82- Rb is alkylene; Q is a leaving group; Cl W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 1- 2 00 *P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

-C(O)NHR

17 where R 17 is loweralkyl, alkylaminocarbonyl, 00 dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido,

-C(O)NHS(Q)

2 Rl 6 where R 16 is loweralkyl, hatoalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(Q)Rl6.

HO 0 0 (HO 0

OH

I N 0 0 0 0 WO 99/06397 WO 9906397PCT/US9815479 -83-

H

CF

3

H

,or M

~NHSO

2

CF

3 an Ri and R2 are independently selected from hydroen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkYl, aminocarbonylalkenyl, alkylaminocarbolylalkell dialkylaminocarbonylalkenYl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)amifloalkYl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic) alkyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or arylalkyl, Rbb is hydrogen or alkanoyl and R C is alkylene, with the proviso that one or both of R, and

R

2 is other than hydrogen; or a salt thereof.

Preferred intermediates include compounds of formula

(VII)

and (ViII) wherein m is zero or 1; R5b is alkylene; Q 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 forrr (VII) and (VilI) wherein n and m are both 0; Rsb is alkylene; Q is a leaving group; W is -C0 2 -G wherein G is hydrogen or a carboxy protecting group; iula WO 99/06397PCIS8 47 PCTIUS98/15479 00 -84and R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or N- unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4-ethoxyphenyl, 4-ethylphenyl, 4- 00 methylphenyl, C\ 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4methoxyphenyl, 3-fluoro-4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 00 4-hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent -is selected from loweralkyl, haloalkyt, alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-Nalkyl)aminoalkyl, and (xiii) alkylsulfonylamidoalkyl, and R 2 is substituted or unsubstituted 1,3-benzodioxolyl, 7-methoxy-1,3benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofurnayl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or the substantially pure or (-)-isomer thereof.

Other compounds which are useful as intermediates for the preparation of compounds of the invention are: R2 ~N R5b

(CH

2 )n

(CH

2 )m (1IX) wherein n is 0 or 1; m is 0 to 6; Rsb is alkytene;

R

20 a 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, Mb -P0 3

H

2 WO 99/06397 WO 9906397PCTIUS98I1 5479 00 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl,

-CN,

ci(e) -C(O)NHRl7 where R17 is loweralkyl, alkylaminocarbonyl, 00 dialkylaminocarboflyl, tetrazolyl, hydroxy, alkoxy, 00 sulfonamido, -C(O)NHS(O)2Rl6 where R16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rie, HO 0 0

H

OH

(p) 0 0 0 H4 WO 99/06397 WO 9906397PCT/US98/15479 00 -86- J~j>-CF., Mt H or 00

NHSO

2

CF

3 Mu and Ri and R 2 are independently selected from hydrogen, loweralkyl, ci alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, 00 haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cI cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonytalkyl, dialkytaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylamnin ocarbonyl al kenyl, hydroxyalkenyl, aryl, arylalkyl, arytoxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic) al kyl and (Raa)(Rbb)N-Rcc- wherein R aa is a ryl 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: R2N .11R 5 b -NHR 2 0a R2N .R5b

VC

2

(CH

2 )Vm (C2) W Ror W R, (X (Xl1) wherein n is 0 or 1; m is 0 to 6; R.Sb is alkylene:

R

2 0a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylaikyl, aryl or arylalkyl; 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, -C N, WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -87- -C(O)NHRl7 where R17i is loweralkyl, alkylaminocarboflI diatkylamilocarboflyl, tetrazolyl, 00 hydroxy, alkoxy, sulfonamido, Cl(1) -C(O)NHS(O)2R16 where R16 is toweralkyl, haloalkyt, 00 0 phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl6, HO 0 0 HO 0

OH

0 0, 0 0 H4 H ,o WO 99106397 PCT/US98/15479 00 -88- 2

CF

3 an R1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyt, hydroxyalkyl, 00 haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, 0 0 dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, cI aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)amifloalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)N-R cc 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.

Preferred intermediates include compounds of formula (X) and (Xl) wherein m is zero or 1; is alkylene; R2Oa is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, Ihaloalkoxyalkyl, 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.

Particularly preferred intermediates are compounds of formula and (Xl) 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 R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxypheflyl, 3-fluoro-4- WO 99/06397 PCT/US98/15479 00 -89- Sethoxyphell 2-fluoropheflyl, 4-methoxymethoxyphelyl, 4- Shydroxypheflyl, 4-t-butylpheflyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxaflyl NI or dihydrobelzofuralYl wherein the substituent is selected from lowera lkyl, haloalkyl, alkoxy, alkoxy,alkoxy and carboxyalkoxy, (ix) 00 aryalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N- Salkyl)aminoalkYl, and (xiii) alkylsulfonylamidoalkYl, and R 2 is Ssubstituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 .3- Sbenzodioxolyl, 1 ,4-beflzodioxaflyl, 8-methoxy- 1,4-benzodioxanyl, 00 dihydrobeni~oUrall benzofurflayl, 4-methoxypherlyl, dimethoxypheflyl, 0 fluoropheflyl or difluoropheflyl 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 benzyloxycarbofll

DBU

for 1,8-diazabicyclo5.4.0]ufdec 7 ene, EDOI for 1-(3dimethylamirnopropyl-3ethylcarbodiimide hydrochloride, EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole. Et 3

N

for triethylamine, TEA for trifluoroacetic acid and THIF for tetrahydrofurari.

Example 1 trans. trans- 2(4Methoxyhenfl)l 4 3-benzodioxol-5-YlI (oprogylam inocarbonylmethyl)-2yrrolidine3-crboxylic acid Examlole 1A Ethyl 24methoxbeflzol4nitrom ethvl-3-( 1.3-benzodioxole-5-Yl~butyrate To ethyl (4-methoxybenz0yl) acetate (23.0 g, 0.104 mol), prepared by the method of Krapcho et al., Org. Syn. A.Z, 20 (1967), and 5-(2nitrovinyl).1,3-beflzodioxole (17.0 g, 0.088 mol) dissolved in 180 mL of toluene and heated to 80 00 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 WO 99/06397 PCT/US98/15479 00

O

chromatography ethyl acetate in methylene chloride) indicated the S absence of nitro starting material. Toluene (200 mL) was added, and c 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 00 chromatographed on silica gel eluting with 3:1 hexane-ethyl acetate to S give 21.22 g of the desired product as a mixture of isomers and 9.98 g.

0 of recovered ethyl (4-methoxybenzoyl)acetate.

00 Example 1B Ethyl 2-(4-methoxvDhenyl)-4-(1.3-benzodioxol-5-vl.-4.5-dihvdro-3H-Dvrrole-3carboxylate The compound resulting from Example 1A (21 g) in 500 mL of ethanol was hydrogenated under 4 atmospheres of hydrogen pressure using a Raney nickel 2800 catalyst (51 (The Raney nickel was washed with ethanol three times before use.) The catalyst was removed by filtration, and the solution was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 8.5% ethyl acetate in methylene chloride to give 12.34 g of the desired product.

Example 1C Ethyl 2-(4-methoxyphenyl-4-(1.3-benzodioxol-5-yl)-oyrrolidine-3-carboxylate) as a mixture of cis-cis; trans.trans: and cis.trans-isomers The compound resulting from Example 1B (11.89 g, 0.324 mol) was dissolved in 27 mL of tetrahydrofuran and 54 mL of ethanol. Sodium cyanoborohydride (2.35 g, 0.374 mol) and 5 mg bromocresol green were added. To this blue solution was added dropwise a solution of 1:2 concentrated HCI in ethanol at such a rate that the color was kept at 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 WO 99/06397 PCT/US98/15479 00 -91-

O

with 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-Methoxvyhenyl)-4-(1.3-benzodioxol-5-yl)-1 00 (proyvlaminocarbonylmethvl)-Dyrrolidine-3-carboxylic acid The mixture of 64% trans,trans- and 34 cis,trans-pyrrolidines (the mixture resulting from Example 1C) (5.72 g, 15.50 mmol), oo ethyldiisopropylamine (4.20 g, 32.56 mmol), and N-propyl 0 bromoacetamide (3.42 g, 19.0 mmol), prepared by-the method of Weaver, S W.E. and Whaley, J. Amer. Chem. Soc., 69: 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 concentrated in vacuo to give 7.16 g of product as a mixture of trans,trans- and cis,trans- ethyl esters.

This mixture was dissolved in a solution of 50 mL of ethanol and mL of water containing 5.00 g of sodium hydroxide and stirred for 3 hours at room temperature. The-solution was concentrated in vacuo and mL of water added. The mixture was extracted with ether to remove the unreacted cis,trans- ethyl ester. The aqueous phase was treated with hydrochloric acid until slightly cloudy. It was then further neutralized with acetic acid to give the crude acid product. The crude product was filtered and purified by dissolving it in tetrahydrofuran, drying over sodium sulfate, concentrating in vacuo, and crystallizing from ether to give 3.230 g of the title compound. m.p. 151-153 'H NMR (CD 3 OD, 300 MHz) 8 0.87 J 7 Hz, 3H), 1.49 (sextet, J 7 Hz, 2H), 2.84 d, J 16 Hz, 1H), 2.95-3.20 4H), 3.20 J 16 Hz, 1H), 3.34-3.42 1H), 3.58-3.66 1H), 3.78 3H), 3.88 J 10 Hz, 1H), 5.92 2H), 6.75 J 8 Hz, 1H), 6.86 (dd, J= 8 Hz, J 1 Hz, 1H), 6.90 J 9 Hz, 2H), 7.02 J 1 Hz, 1H), 7.40 J 9 Hz, 2H).

Example 2 trans.trans-2-(4-MethoxvDhenyl)- 4 .3-benzodioxol-5-vyl-1 -(aminocarbonvlmethvl)pyrrolidine-3-carboxvlic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans-pyrrolidines (the mixture WO 99/06397PC/S8I47 PCTIUS98/15479 00 -92resulting from Example 10), 220 mg of diisopropylethylamine and 184 mg iodoacetamide were reacted at 45 OC 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 00 unreacted cis,trans- ethyl ester. The isolation and purification procedures described in Example 1 D were used to give 134 mg of the 0 title compound. m.p. 246-248 0 C. I H NMR (DMSO-d 6 300 MHz) 8 2.61 (d, 00 J 16 Hz, 1 2.71 J 9 Hz, 1 2.90 J 9 Hz, 1 2.98 J= 16 Hz, I1H),3.25-3.35 (in, I1H), 3.45-3.55 (in, 1 3-71 3H), 3.75 (di, J= Hz, 1H), 6.00 2H), 6.81 2H), 6.90 J 8 Hz, 2H), 7.10 1H), 7.17 1 7.34 1 7.38 J 8 Hz, 2H).

Examole 3 trans. trans-2-(4- Meth oxvoh enyl) -44(1 .3-ben zodioxol-5-F)- 1 (4-f Iuo robe nzyfl) pvrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg of the mixture of 64% trans,trans- and 34% cis,trans- pyrrolidines (the mixture resulting from Example 10), 220 mng of diisopropylethylamine and 185 mg of 4-fluorobenzyl bromide were reacted at room temperature for 3 hours in 1 mL of acetonitrile to give 387 mg of a mixture of trans,trans- and cis, trans- N-al kylated esters. A portion (360 mg) was hydrolyzed with 250 mng NaOH in 1 mL of water and 4 mL of ethanol to give 160 mng of the title compound as an amorphous powder. 'H NMR

(CDCI

3 300 MHz) 8 2.74 J 9 Hz, 1H), 2.95 J 7 Hz, 1H), 2.98 J 14, 1 3.07 (dd, J 9 Hz, 1 Hz, 1 3.42-3.53 (mn, 1 3.70 J 9 Hz, 1 3.78 J 14, 1 3.81 3H), 5.92 2H), 6.70 J 8 Hz, I1H), 6.77 (dd, J 8 Hz, 1 Hz, 1 6.91 J 9 Hz, 2H), 6.94 -7.00 (in, 3H), 7.20 7.25 1 7.44 J =9 Hz, 2H).

Examlole 4 trans. trans-2-(4-Methoxyvohenvl)-4-( 1. 3-benzodioxol-5-fl)- 1 -(2-ethoxvethYfLpvrrolidine-3-carboxylic acid Using the method described in Example 1D, 300 mg. of the mixture of 64% trans,trans- and 34% cis, trans-pyrrolidines (the mixture resulting from Example 10), 220 mg of diisop ropyl ethyl amine and 152 mng of 2-bromoethyl ethyl ether were ref luxed in 1 .5 mL acetonitrile for WO 99/06397 PCTIUS98/15479 00 -3 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.

m.p. 88 90 00. 1 H NMR (OD0 3 300 MHz) 8 1.25 J 7 Hz, 3H), 2.21 2.32 (in, 1H), 2.70-2.80 (in, 2.85-2,94 (in, 2H), 3.38-3.55 (in, 6H), 00 3.67 J 10 Hz, 1H), 3.79 3H), 5.94 2H), 6.72 J 8 Hz, 1H), 6.84 (in, 1 6.84 J 9 Hz, 7.08 J 1 Hz, 1 7.33 J 9 Hz, 2H).

00 Example Nl trans. trans-2-(4-Methoxyghenyl-4-( 1.3.benzodioxol-5-yl)- 1 -(2-Qrogoxyethyl)gyrrolidine-3-carboxylic acid Using the method described in Example 1D, 520 mg of the mixture resulting from Example 1C, 364 mng of diisopropylethylaine, 50 mng potassium iodide and 350 mg 2-chloroethyl 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 mng NaOH in 1 mL of water and 4 mL of ethanol to give 225 mng of the title compound as an amorphous powder. 'H NMR (CDCI3, 300 MHz) 8 0.87 J 7 Hz, 3H), 1.53 (sextet, J 7 Hz, 2H), 2.28-2.41 (mn, 1H), 2.71-2.83 (mn, 1H), 2.92-3.08 (mn, 2H), 3.30 J 7 Hz, 2H), 3.40-3.60 (in, 4H), 3.72-3.83 (mn, 1H), 3.76 3H), 5.92 2H), 6.71 J 8 Hz, 2H), 6.74 (dd, J 8 Hz, 1 Hz), 6.71 J 9 Hz, 2H), 7.07 Kd J 9 Hz, 2H), 7.73 J 9 Hz, 2H).

trans, trans-2-(4-Methoxyghenyl)-4-( 1. 3-benzodioxol-5-yll- 1 -r2-(2methoxvethoxy)ethyll-Oyrrolidine-3-carboxylic acid Eape6 Ethyl trans, trans-2 4-methoxyrhenyl)-4- (1 .3-benzodioxol-5-fl) grrolidine-3carbox late 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 chromatography in ethyl acetate indicated the absence of starting material. The NaQEt was neutralized WO 99/06397 PCT/US98/15479 00 -94with HCI in ethanol, and the solution was concentrated in vacuo. The S residue was taken up in toluene and extracted with potassium N 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).

o0o Example 6B (Ni trans.trans-2-(4-Methoxvohenyl)-4-( 1.3-benzodioxol-5-yl-1-2-(2- 00 methoxvethoxv)ethvll-pyrrolidine-3-carboxylic acid O 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 the trans, trans-ester. A portion (200 mg) was hydrolyzed with 125 mg NaOH in 1 mL of water and 2 mL of ethanol to give 151 mg of the title compound as an amorphous powder. 'H NMR (CD30D, 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-Methoxyohenyl)-4-( 1.3-benzodioxol-5-vl)-1 -[2-(2-oyridyl)ethyl]pyrrolidine-3-carboxylic acid The compound resulting from Example 6A (250 mg), 2-vinyl pyridine (355 mg) and one drop of acetic acid were dissolved in 2methoxyethanol, and stirred at 100 °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 OC.

1H NMR (CD 3 OD, 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), RO (dd. J 8 Hz. 1 Hz), 6.85 J 9 Hz, 2H), 6.92 J 1 Hz, 1H), WO 99/06397 PCTIUS98/1 5479 00 0 7.20 J 9 Hz, 2H), 7.20-7.32 2H), 7.70-7.80 2H), 8.40 J 4 Hz, 1H).

Example 8 trans.trans-2.(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-vl)-1 -(moroholin-4- Sylcarbonyl)-Dvrrolidine-3-carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg 0 triethylamine dissolved in 2 mL of methylene chloride and cooled in an 00 ice bath was added 146 mg 1-morpholinocarbonyl chloride. The mixture was stirred 3 hours at room temperature. Toluene- was added and the S 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 0 C. 1 H NMR (DMSOd6, 300 MHz) 8 2.96 (dd, J 12,Hz, 13 Hz, 1H), 3.03-3.13 2H), 3.20- 3.30 2H), 3.40-3.60 5H), 3.74 3H), 3.70-3.85 3H), 5.10 (d, J 10 Hz, 1H), 5.99 J 1 Hz, 2H), 6.80-6.90 2H), 6.87 J 9 Hz, 2H), 7.07 1H), 7.25 J 9 Hz, 2H).

Example 9 trans.trans-2-(4-Methoxyphenyl)- 4 -(1,3-benzodioxole-5-vl)-1 -(butvlaminocarbonyl pyrrolidine-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 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 'H NMR (DMSOd6, 300 MHz) 8 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).

WO 99/06397 PCT/US98/15479 u -96- Example C trans. trans-2-(4-Methoxyohenvyl-4- 1.3-benzodioxol-5-ylv-1 C methoxyohenylaminocarbonyl)-3-oyrrolidine-3-carboxylic acid The compound resulting from Example 6A (300 mg) was treated 0 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.

Sm.p. 185-187 1 H NMR (CDCI 3 300 MHz) 8 3.23 (dd, J 12 Hz, 13 Hz, 0 0 1H), 3.55-3.68 2H), 3.72 3H), 3.83 3H), 4.50-4.65 1H), O 5.06 J 10 Hz, 1H), 5.90 1H), 5.95 1H), 6.72 J 9 Hz, 2H), 6.7-6.8 3H), 6.92 J 9 Hz, 2H), 6.97 J 9 Hz, 2H), 7.37 J 9 Hz, 2H).

Example 11 trans. trans-2-(4-Methoxohenvl)-4-( 1.3-benzodioxol-5-vli-1 -acetvlovrrolidine-3carboxvlic acid The compound resulting from Example 6A (250 mg) in 0.5 mL of toluene was treated with 200 mg of acetic anhydride. After stirring 2 hours at room temperature, water was added and the acetic acid :o neutralized with potassium bicarbonate. The mixture was extracted with toluene to give 273 mg of the intermediate ester. A portion of the ester (200 mg) was hydrolyzed using the method of Example 1D to give 211 mg of the title compound, m.p. 248-250 Rotational isomers are seen in the NMR. 'H NMR (DMSO-d6, 300 MHz) 8 1.55 and 2.00 3H), 2.94 and 3.03 (dd, J 12 Hz, 13 Hz, 1H), 3.3-3.6 2H), 3.72 and 3.76 3H), 4.12 and 4.28 (dd, J 12 Hz, 7 Hz, 1H), 4.95 and 5.04 J 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).

Example 12 trans trans-2-(4-Methoxyphenvl)-4-( 1.3-benzodioxol-5-vl)-1 (2-furoyl)-Dvrrolidine-3carboxylic acid To the compound resulting from Example 6A (300 mg) and 164 mg triethylamine dissolved in 2 mL methylene chloride and cooled in an ice bath was added 138 mg of 2-furoyl chloride. The mixture was stirred minutes at room temperature and then worked up by the procedures described in Example 8 to give the intermediare ester. The ester was WO 99/06397 PCTIUS98/15479 -97hydrolyzed by the procedure described in Example 1 D to give 269 mg of the title compound as an amorphous powder. 1 H NMR (DMSO-d6,, 300 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, 1 6.67.4 (in, 8H), 7.8-7.9 (mn, 1 H).

Examile 13 trans, trans-2 Met hoxgh en yl)- 4 -(l.3-benzodioxoI- 5-yi)- 1 (o~henylaminocrbonvl')-Dyrrolidine3-carboxylic acid Starting with the compound resulting from Example 6A, phenyl isocyanate and the procedures described in Example 9, the title compound was prepared. in.p. 209-21 1 00.. 1H NMR (DMS0-d6, 300 MHz) 8 3.03 (dd, 1 3.55 (in, 1 3.70 (mn, 1 3.72 3H), 4.15 (in, 1 H), 5.13 1 6.00 6.88 (mn, 5H), 7.07-7.20 (in, 3H), 7.30 2H).

7.38 2H), 8.20 (bs, 1 H).

Examole 14 trans, trans-2-(4-MethoxVghenYfl4 (1 .3-benzodioxol-5-yl)- 1- (allylaminocarbonylmlethyWD-grrolidine3carboxlic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 138-140 OC. I H NMR (CDC1 3 300 MHz) 8 2.84 (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 (in, 1H), 5.97 2H), 6.74- 6.97 (in, 7.38 2H).

Exmple trans. trans-2 (4 -M eth oxyh env1)- 4- 3-ben zodioxol-5-yfl 1 (nbutylam inoca rbonylm ethyfl)-Dyrrol idi ne3carboxyl c acid Using the procedures described in Example 1 the title compound was prepared. m.p. 105-107 00. 1 H NMR (CDC13, 300 MHz) 8 0.90 3H), 1.30 (mn, 2H), 1.45 (in, 2H), 2.80 2.87-3.35 (in, 6H), 3.62 (in, 1H), 3.80 3H), 5.97 2H), 6.75-6.92 (mn, 5H), 7.28 2H).

Examp~le 16 trans. trans-2-(4-MethoxyphenYl)- 4 .3-benzodioxol-5-yfl- 1 -(N-(n-12rolylI-NiethylainocarboflylmethylP1yrrolidine 3-carboXylic acid Using the procedures described in Example 1 the title compound was prepared as an amorphous solid. Rotational isomers are seen in the WO 99/06397 WO 9906397PCT/US98/15479 00 -98- NMR. 1 H NMR (CDCI3, 300 MHz) 8 0.73, 0.84 (2t, 3H), 1.49 (in, 2H), 2.80 (dd, 11-1), 2.85 (2s, 3H), 2.95-3.20 (in, 3H), 3.20-3.40 (in, 1 3.40 (d, 1 3.60 (in, 1IH), 3.79 3H), 5.93 2H), 6.73 I1H), 6.86 (in, 2H-), 7.03 (in, 1 7.32 2H).

00 Examlle 17 trans-2- Methoxyph eny (1 benzodioxoI- 5-yfl -1 (pyrro lid in- 1 00 ylcarbonylmethyl)-Dyrrolidile-3-carboxylic acid Using the procedures described in Example 1 the title compound CI was prepared as an amorphous solid. 1 H NMR (COVC3, 300 MHz) 8 1.40- 1.70 (in, 6H), 2.80 I1H), 3.00 (in, 2H), 3.24-3.43 (in, 5H), 3.60 (in, 2H), 3.73 IH), 3.80 3H), 5.95 2H), 6.74 1H), 6.80-6.90 (in, 3H), 7.04 1 7.30 2H).

Examgle 18 trans, trans-2-(4-Methoxyrheflyfl-4-(1 .3.benzodioxol-5-yl)- 1- 0isobutlam inocarboflyl ethyl) yrrolidile--c arboxyl ic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 175-177 OC. 1H NMR (CD 3 OD, 300 MHz) 8 0.87 (dd, 6H), 1.75 (septet, 1H), 2.85 1H), 2.90-3.10 (in, 4H), 3.23 1H), 3.40 (mn, 1 3.58-3.67 (mn, 1 3.78 3H), 3.89 1 5.92 2H), 6.76 1 6.86 (dd, I1H), 6.91 2H), 7.02 1 7.40 2H-).

Examlole -19 trans, trans-2 4- Met ho xyphgn l)f-4- (1 .3ben zodioxol- 5-yi)- 1- (cyclogentlamilocarbolYlmethyl)-DYrrolidile-3-carboxylic acid Using the procedures described in Example 1 the title compound was prepared. m.p. 137-139 OC. I H NMR (CDCI3. 300 MHz) 8 1.34 (in, 2H), 1.62 (in, 4H), 1.90 (mn, 2H), 2.76 1H), 2.90 1H), 3.04 (dd, 1H), 3.22 1 3.28 (dd, 1 3.40 (in; 1 3.80 3H), 4.15. (in, 1 5.97 2H), 6.75-6.95 (in, 5H), 7.27 (mn, 2H).

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -99- Example trans, trans-2-(4-Methoxyghenyfl-4-( 1.3-benzodioxol-5-y')-1 -(morphglifl-4ylaminocarbonylmethyl-Yrrolidile-3-carboxylic acid Usin g the procedures described in Example 1 the title compound was prepared as an amorphous solid. 'H NMR (CDCI3, 300 MHz) 8 2.82 (d, 00 3.00 (in, 2H), 3.24 (in, 1H), 3.30-3.52 (in, 4H), 3.52-3.75 (in, 8H), 3.80 3H), 5.95 2H), 6.75 1 6.84 3H), 7.00 1 7.28 (d, 2H).

00 Examlle 21 trans. trans-2-(4-Methoxvr-henl)f-4-( 1.3-benzodioxol-5-yl)-1 -(2-g~henoxyeQthl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared as an amorphous solid. 1 H NMR (CD 3 OD, 300 MHz) 8 2.82 (mn, 1H), 2.96 (dd, 1H), 3.13 (mn, 1H), 3.32 (mn, IH), 3.51-3.70 (in, 2H), 3.77 3H), 4.00 1H), 4.07 (in, 2H), 5.91 2H), 6.72 1H), 6.80-6.95 (in, 6H), 7.03 1 7*22 (dd, 2H), 7.39 2H).

Examlle 22 trans, trans-2-(4-Methoxyghenl)f-4-( 1.3-benzodiol-5-y')-1 methoxyethylainogarbonlmethyl)-DYrrolidife3carboxylic 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, 1 H)I 2.97 2H), 3.21 1 3.38 (in, I1H), 3.32 3H), 3.44 (in, 4H), 3.62 (in, I1H), 3.79 3H), 3.86 1 5.93 2H), 6.76 1 6.85 (cid, 1H), 6.91 2H), 7.01 (di, 1H), 7.38 2H).

Example 23 trans. trpns.-2-(4-Methoxylhel)-4-( 1.3-benzodioxol-5-yl')- 1 -(2-butoxyethl)pyrrolidine-3-carboxylic acid Using the procedures described in Example 4 the title compound was prepared. m.p. 53-55 00. 'H NMR (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 (ti, J=6Hz, 6Hz, 1H), 2.92 J=lOHz, 3.35 J=7Hz, 2H), 3.42-3.56 (in, 4H), 3.68 J=lOHz, 1H), 3.78 3H), 5.94 2H), 6.73 J=8Hz, 1H), 6.83 (di, J=9Hz, 2H), 6.82-6.87 (in, 1H), 7.06 (di, J=2Hz, 1H), 7.32 (di, J=9Hz, 2H). MS in/e 442 (M+H)4.

WO 99/06397 WO 996397PT[US98II 5479 00 -100- Example 24 trans, trans-2-(1 .3-Benzodioxol-5-yP)-4-(4-mgtho~yghenyl)-1! (oroovilam inocarbonvlm ethyI)-ovyrrolidine-3-carboxylic acid 00 Using the procedures described in Example 1 and substituting ethyl (1,3-benzodi OxOl-5-ylcarboflyl) acetate for ethyl (4acetate and 4-(2-nitrovinyl)anisole for 5-(2- NI nitrovinyl)-1 3-benzodioxol-5y1 afforded the title compound. m.p. 97- 00 099 0 C. IH NMR (CDCI3, 300 MHz) 8 0.78 J=7Hz, 3H), 1.39 (sextet, ci J=7Hz, 2H), 2.72 J=l6Hz, 1H), 2.74 J=lOHz--' 1H), 2.80-3.10 (in, 4H), 3.26-3.38 (in, 1H), 3.53 (in, 1H), 3.73 3H), 3.80 J=lOHz, 2H), 7.80 J=6Hz, 1H). MS (001/NH 3 in/e 441 trans, trans-2-( 1.3 Ben zodioxo-5yfl-4-(4-m ethoxylhenyl)l oroooxyethyflpyrrolidine-3-carboxylic acid Using the procedures described in Example 5 and substituting ethyl 3-benzodioxol-5-ylcarboflyl) acetate for ethyl (4methoxybenzoyl) acetate and 4-(2-nitrovinyl)aniSOle for 5-(2nitrovinyl)-1,3-benzodioxo-5yl afforded the title compound. in.p. 67- 6900C. IH NMR (0D013, 300 MHz) 8 0.89 J=7Hz, 3H), 1.56 (sextet, J=7Hz, 2H), 2.33 (in, 1H), 2.78-3.00 (in, 3H), 3.32 J=7Hz, 2H), 3.45- 3.57 (in, 4H), 3.73 (in, 1H), 3.79 3H), 5.93 2H), 6.22 J=8Hz, 1H), 6.85 J=8Hz, 3H), 6.98 1H), 7.37 J=8Hz, MS (D01/NH 3 m/e 428 Example 26 trans. trans-2-( 1.3-Benzodioxol-5-yl)-4-(4-methoxylhefl)l- methoxyetho xy) ethl) I- yrrolidile-3-carboxylic acid Using the procedures. described in Example 4 and substituting the starting materials described in Example 25 and using 2-(2methoxyethoxy)ethylbromide to alkylate the pyrrolidine nitrogen afforded the title compound. m.p. 85-86 OC. 1 H NMR (CD 3 0D, 300 MHz) 8 3.18-3.90 (mn, 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 in/e 444 WO 99/06397 PCTIUS98/15479 00 -101- Example 27 trans. trans-2-(1 .3-Benzodioxl.5.VIl)-4-(4-methoxyghenl)-1 -(butoxvethyl)- Dyrrolidine-3-carboxylic acid Using the procedures described in Example 4, substituting the 00 starting materials described in Example 25 and using 2ethoxyethylbromide to alkylate the pyrrolidine nitrogen afforded the 0 title compound. m.p. 54-56 00. 1 H NMR (CDC13. 300 MHz) 6 0.89 J- 00 7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 1.52 (pentet, J=7Hz, 2H), 2.40 (in, 1H), 2.74-2.98 (mn, 3H), 3.46 J=7Hz, 2H), 3.42-a.56 (in, 4H), 3.68 (d, J=1l-Iz, 1H), 3.80 3H), 5.93 (dd, J=6Hz, 1Hz, 2H), 6.72 J=8Hz, 1H), 6.74 (dd, J=9Hz, 3H), 6.96 1H), 7.36 J=9Hz, 2H).

Examole 28 trans, trans-2-(4-Mthoxyrhel-4-( 1.4-benzodioxa'-6-y)-1- (grooyl am inoca rbolylm ethyl) yrrol idifle-3-carboxylic acid Using the procedures described in Example 1 and substituting 6- (2-nitrovinyl)-1 ,4-benzodioxane 'for 5-(2-nitrovinyl)-1 ,3-benzodioxole afforded the title compound. m.p. 80-81 00. IH NMR (CDC13, 300 MHz) 8 0.89 J-7Hz, 3H), 1.49 (sextet, J=7Hz, 2H), 2.78 J=l6Hz, 1H), 2.92 J=lOHz, IH), 3.05-3.43 (in, 5H), 3.24 J=l6Hz, 1H), 3.52-3.62 (mn, 1H), 3.80 3H), 3.80 J=lOHz, 1H), 4.27 4H), 6.74-6.93 (in, 7.29 J=9Hz, 2H). MS (DCI/NH3) m/e 455 Examgle 29 trans. trans-2- Methoxvohenyl)-4- 4-benzodioxan-6-y)- 1 -(N-methyl-Ngropylpminocarbolvlmethyfl)pyrrolidie3-carbo~lic 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-mnethyl- N-pro pyl bromoacetamide afforded the title compound. m.p. 74-76 OC.

Rotational isomers are seen in the NMR. 'H NMR (CDCI3, 300 MHz) 0.73, 0.83 (2t, J=7Hz, 3H), 1.48 (in, 2H), 2.78 (dd, 2.85 (2s, 3H), 2.96-3.15 (in, 3H), 3.27-3.42 (in, 3H), 3.52-3.60 (in, 1H), 3.75 1H), 3.78 4.22 4H), 6.80-6.98 (mn, 5H), 7.32 2H). MS (DCI/NH 3 m/e 469 WO 99/06397 PCTIUS98/15479 00 -102- Exam 3 trans. trans-2-(4-Methoxypheflyl)-4-(1 .3-benzodioxol-5-yfl- 1 -(N-methyl-Nbutylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid ClUsing the procedures described in Example 1, the title compound was prep ared. Rotational isomers are seen in the NMR. IH NMR (CD3OD, 00 300 MHz) 8 0.86 (2t, 3H), 1.04-1.50 (in, 4H), 2.85 (2s, 3H), 2.93-3.20 (in, 4H), 3.40 (in, 2H), 3.52 (dd, 1H), 3.60 (in, 1H), 3.80 3H), 3.85 (in, 11H), 5.91 2H), 6.74 1H), 6.83-6.95 (in, 3H), 7.03 1H), 7.35 (dd, 2H).

00 0 trans, trans-2-(4-MethoX -2methoxMepthoXyghenyl)-4-(1.3-benzodioxol-5-fl)- 1 methvl-N-butylaminocarbonYliethylI-Oyrrolidine 3 carboxylic acid Ethyl 2(4methoxy-2-methoXyinethoXyphenl- 4 (1 Using the procedures described in Examples 1 A and 1 B and substituting ethyl (4-inethoxy-2 -m ethoxym ethoxyben zoyl) acetate for ethyl methoxyben zoyl) acetate afforded ethyl 2-(4-methoxy-2- I methoxymethoxyphenYl) 4 -(l,3-benzodioxol-5-yl)-4,5-dihydro-3Hpyrrole-3-carboxylate.

The above dihydro pyrrole carboxylate (3.0 g, 7.0 mmol) 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 afford the title compound (1.9 g, 63%) as the cis-cis isomer.

trans. trans-2 4Methoxy-2-methoXyinethoXyghenl)l 4 (1 .3-benzodioxol-5-y')- 1 4WN m ethyl- N-b utyl am inocarbonyl methyl) -12rrolidile-3-carboxylic acid The compound resulting from Example 31 A was epimerized by the procedure described in Example 6A. The resulting trans,trans compound (100 mg, 0.23 iniol) was then reacted by the procedures described in Example ID substituting N-methyl-N-butYl bromoacetainide for Npropyl bromoacetam~ide to give the title compound (75 mg, m.p.

65-67 OC. Rotational isomers are seen in the NMR. 1 H NMR (CDCI3. 300 WO 99/06397 WO 9906397PCTIUS98/15479 00 -103- MHz) 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, 6H), 3.50 3H), 3.43- 3.65 (mn, 2H), 3.78 3H), 4.30 J=7Hz, I1H), 5.09 J=7Hz, 2H), 5.92 2H), 6.55 (dd, J=3Hz, 1 6.68 I1H), 6.72 1IH), 6.85 (2t, J=1lHz, 00 1H), 7.04 J=lHz, 1H), 7.42 (dd, J=3Hz, 1H).

Example 32 CI trans. trans-2-(4-MethoXylhelyl)-4-(1I.3-benzodioxol-5-yV)- 1 -(3-ethoxygroovF)- 00 12yrrolidin-5-one-3-carbo~ylic acid Examgle 32A Ethyl 2- (4-m ethoxyben zol-3-carbom eth oXy- 1. 3-be nzodi oxol e- 5-1roP !onate To ethyl (4-m ethoxybeflzOyl) acetate (4.44 g, 0.02 mmol) dissolved in 20 mL of anhydrous THF was added in portions 480 mg of NaH. The mixture was stirred .for 30 minutes under nitrogen at ambient temperature. Methyl (1 ,3-benzodioxol-5-yi) bromoacetate (5.46 g, 0.02 mol) in- 5 mL of THF was added. The mixture was stirred overnight at ambient temperature, diluted with 200 mL of EtOAc, and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound (7.67 g, 92%) which was used without further purification.

Examgle 32B Ethyl I -(3-ethox roovl2(4-inethoxYghenyl)- 4 (1.3-benzodioxol-5-yfl-4 5-oxo- 1 H-12yrrole-3-carbogylate A mixture of the compound resulting from Example 32A (700 mng, 1.69 iniol), 3-ethoxypropyl amine (348 mng, 3.38 mmol) and 1 mL of acetic acid in a sealed tube was heated for 18 hours at 125 After cooling the contents of the tube to ambient temperature, 5 mL of water was added and the mixture extracted with ethyl acetate (2x100 inL).

The. combined organic extracts were washed with saturated so'dium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chroinatographed on silica gel eluting with 3:2 hexane-ethyl acetate to give 330 ing of the title compound.

WO 99/06397 WO 9906397PCTIUS98II 5479 00 -104- Ct E~xamgle 2C Ethyl 1 -(3-ethoxyo2rgpvll-2-(4-methoXYhenfl)l 4 -(l.3-benzodioxol-5-y-Dyrrolidifl-5- N one-3-carboXylate Th e compound resulting from Example 32B (300 mg, 0.64 mmol) in 00 15 mL of methanol was reduced with 100 mg of 10% Pd/C under hydrogen for 3 hours at ambient temperature. The catalyst was I removed by filtration and the filtrate was concentrated under reduced Ni pressure to give the title compound.

00 c-iExample 32 trans, trans-2- (4-M eth oxygh enl)-4-( 1.3- ben zod ioxol-5-M) -I (3-ethogxyDropyl) pyrrolidin-5-one-3-carboXylic acid To the compound resulting from Example 32C (100 mg, 0.21 mmol) dissolved in 1 mL of ethanol was added 3 drops of a solution of 21 sodium ethoxide in ethanol. The mixture was heated to 70-80 0 IC 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 Mr HCI and allowed to stand overnight. The white crystalline solid was collected by filtration to give the title compound (60 mg, m.p.

134-140 OC. 1 H NMR (DMSO-d6, 300 MHz) 8 1.04 J=7Hz, 3H), 1.55 (sextet, J=7Hz, 2H), 2.48-2.56 (mn, 1H), 2.93 (dd, J=9Hz, 1H), 3.25 (t, J=7Hz, 2H), 3.28-3.40 (in, 2H), 3.48-3.57 (in, 1H), 3.78 3H), 3.88 (d, J=lOHz, 1H), 4.72 J=lOHz, 1H), 6.02 2H), 6.74 (dd, J=8Hz, 1Hz, 1H), 6.87 J=8Hz, 2H), 6.98 J=8Hz, 2H), 7.38 J=8Hz, 2H). MVS

(DCI/NH

3 m/e 442 Examgle 33 trans. trans-2-(4-MethohyohenlW4-( 1.3-benzodioxol-5-VFI- 1 -(3-methoxybenl)lgyrr lidin-5-one-3-carboxylic acid Following the procedures described in Example 32 and substituting 3-methoxybenzylamline for 3-ethoxypropylainine afforded the title compound (123 mg, m.p. 150-152 OC. 'H NMR (CD 3

OD,

300 MHz) 8 2.96 (dd, J=8Hz, 10Hz, 1H), 3.72 3H), 3.80 4.06 (d, ^UH 1H). 4.92 J=l6Hz, 2H), 5.92 2H), WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -105- 6.55-6.63 (in, 2H), 6.82 J=BHz, 4H), 6.94 J=8Hz, 2H), 7.15-7.22 (in.

S 3H). MS (DCIINH3) mWe 475 00 trn.tas2-4 ehxvphenyl)-4-( 1.3-benzodioxol-5-yl)-l1-(N.

N-

diisoamylam inocarbonylm ethyl)-pyrrolidile-3carbogylic acid title compound was prepared as an amorphous solid using the 00 procedures described in Example 1. 1H NMR (0D013, 300 MHz) 8 0.70 0.90 (mn, 12H), 1.10-1.60 (in, 10H), 2.75 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.15 3.30 (mn, 2H), 3.40 J=lOHz, 1H), 3.40 3.52 (in, 2H), 3.55 -3.62 (mn, 1H), 3.75 J=12 Hz, 1H), 3.79 3H), 5.93 (dd. J =1 Hz, 3 Hz, 2H), 6.72 J=8Hz, 1K), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 1H), 7.30 J=9Hz, 2H).

trans. trans-2-(4-MethoX henyl)-4-(l .3-benzodioxol-5-yfl-.1

N-

d ioenlylam inocrbolyinethyl)-pyr rolid in e3ca rbo(yl ic Acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1H NMR (CDCI3, 300 MHz) 5 0.82 J 7Hz, 6H), 0.95-1.03 (mn, 2H), 1.10-1.30 (mn, BK), 1.40-1.51 (in, 2H), 2.72 J=l3Kz, 1H), 2.90-3.08 (in, 4H), 3.25-3.50 (mn, 3H), 3.37 (d, J=l3Hz, 1K), 3.52-3,60 (in, 1K), 3.70 J=lOHz, 1H), 3.75 3H), 5.92 (dd, J=2Hz, 5Hz, 2H), 6.72 J=8Hz, 1K), 6.80-6.88 (in, 3H), 7.03 (d, J=2Kz, 1K), 7.30 J=9Kz, 2H).

trans, trans-_2-(4-Methoxyphenyfl 4 .3-benzodioxol-5-yfl-l .N-di(2m ethoyethy 1) m iocarbonylm ethyl)- yrro idin e3ca rboxyl ic acid The title compound was prepared using the procedures described in Example 1. m.p. 120-122 OC. 1 H NM R (CDC13, 300 MHz) 6 2.82 (d, J=13, 1K), 2.94-3.08 (in, 2K), 3.12 3H), 3.23 3K), 3.20-3.70 (in, 11lH), 3.73 J=I OHz, 1KH), 3.79 3H), 5.92 (dd, J= 2Hz, 2Hz, 2H), 6.72 J=8Kz, 1KH), 6.80-6.90 (mn, 3H), 7.04 J=2Kz, 1KH), 7.30 J=9Hz, 2H).

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -106- Eample 3 trans. trans-2-(4-MethonphelYl)-4-( 1.3-benz.odioxol-5-yi')-l1-(2-hexynyl)-Dyrrolidine- Using the procedures described in Example 4, 200 mg. of the pure 00 trans,trafls isomer, the compound resulting from Example 6A was reacted with 109 mg of 1 -bromo-2-hexyfle, prepared by the method in Perkin 1, 2004 (1987), for 1 hour at 55 0 C, to give 226 mg 00 of the intermediate ester. The ester was hydrolyzed using NaOH in 0 ethanol-water for 3 hours at room temperature to give 175 mg of the ci title compound. 1H NMR (CDC13, 300 MHz) 8 J=7Hz, 3H), 1.54 (in, 2H), 2.14-2.22 (in, 2H), 2.96 (dd, J=7Hz, 13Hz, 1H), 3.07 (dd, J=l8Hz, 2Hz, 1H), 3.15 (dd, J=9Hz, 2Hz, 1H), 3.26 J=9Hz, 1H), 3.36 (dd, J 18 Hz, 2Hz, 1H), 3.47-3.55 (in, 1H), 3.79 3H), 3.88 J=9Hz, 1H), 5.95 2H), 6.72 J=8Hz, 1H), 6.80-6.88 (in, 3H), 7.03 J=2Hz, 1H), 7.22 J=9Hz, 2H).

trans, trans-2-(4-Methoxygheflyfl- 4 1.3-benzodioxol-5-Vl)-1 1-(N-cYclooroovlmethYL- N -12rogylam inaca-rbonylm ethyl)- gyrro Iid i ne-3-ca rbo)(Ylic acid The title compound was prepared using the procedures described in Example 1. in.p. 167-169 0 C. Rotational isomers were seen in the NMR. 1 H NMR (CDC13, 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), 2.72 J=l3Hz, 1H), 2.85--3.29 (in, 4H), 3.30-3.50 (in, 3H), 3.52-3.62 (in, 1H), 3.65-3.73 (2 doublets, J=lOHz, 2Hz, 1H), 3.78 3H), 5.95 (2 singlets, 2H), 6.72 (2 doublets, 2H), 6.80-6.90 (in, 3H), 7.00 and 7.05 (2 doublets, J=9Hz, 2H).

Exam~i 3 trans. trans-2-(4-Methoxylhenvi)- 4 .3-benzodioxol-5-yfl- 1 ethyl- No2entyl minocarbonylmethyl)-Dyrrolidife3carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1 H NMR (CDC13, 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 (mn, 3H), 3.22-3.45 (mn, 3H), 3.52- 3.62 (in, 1, 1.7 n 2 -7r)tat 1I .75 and 3.76 (2 singlets, 3H), 5.92 WO 99/06397 WO 9906397PCT/US98/I 5479 00 -107- S(2 singlets, 2H), 6.72 J=BHz, 1IH), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1 7.30 J=9Hz, 21-).

00 trans, trans-2-(4-Methoxyphelyl)-4-( 1.3-benzodioxol-5-y)- 1 Ndisobutylam inocarbonylmethflD1yrrolidile-3-carboxylic acid The title compound was prepared using the procedures described N~ in Example 1. m.p. 141-143 OC. I H NMR (CDCI3, 300 MHz) 0.54 (d, 00 S J=7Hz, 3H), 0.70-0.90 (3 doublets, J=7Hz, 9H), 1.60-1.75 (in, 1H), 1.90- S 2.02 (in, 11H), 2.67 J=l3Hz, 1H), 2.70 J=l3Hz, 1H), 2.84 (dd, J=6Hz, 15Hz, IH), 2.96-3.06 (mn, 2H), 3.20 (dd, J=9Hz, 15Hz, 1H), 3.35 (dd, J=2Hz, 10Hz, 1H), 3.44-3.60 (in, 4H), 3.70 J=9Hz, 1H), 3.79 (s, 5.94 (dd, J=2Hz, 2Hz, 2H), 6.72 J=9Hz, 1H), 6.82-6.90 (in, 3H), 7.03 J=2Hz, 11H), 7.31 J=9Hz, 2H).

Examl~e41 trans. trans-2-(4-Methoxyhel)f-4-(1 .3-benzodigxol-5-ylI- 1 -(N-methvl-N-(2- U rogynyl) am inocarboflylm ethyflD-yrro lid inle3-carbo Xyl ic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. 1 H NMR (CDCI3, 300 MHz) 8 2.09 and 2.32 (2 triplets, J=2Hz, 1 H), 2.80-3.10 (in, 3H), 2.90 and 2.99 (2 singlets, 3H), 3.35-3.50 (in, 2H), 3.52-3.62 (mn, 3.78 3H), 4.03 J=l3Hz, 4.00-4.30 (in, 3H), 5.93 2H), 6.72 (2 doublets, J=8Hz,,1H), 6.80-6.90 (mn, 3H), 7.02 and 7.11 (2 doublets, J 2Hz, 7.30 (2 doublets, J=9Hz, 2H).

Exam Dle 42 trans. trans-2- Meth oxyhanyl'- 4 1.3-be nzod ioxol-5-yll- 1 (N-inethyl- N-(n hexyl~aminocarboflylinethyl)-pyrrolidine3-carbogcylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CDCI3, 300 MHz) 0.85 (2 triplets, J=7Hz, 3H), 1.00-1.50 (mn, 8H), 2.72-2.82 (2 doublets, J=l3Hz, 2.81 and- 2.86 (2 singlets, 3H), 2.92-3.20 (in, 3H), 3.22-3.45 (in, 3H), 3.52-3.62 (mn, IH), 3.72 (2 doublets, 1H), 3.75 and 3.76 (2 singlets 3H), 5.94 (2 singlets, 2H), 6.72 J=BHz, 1H), 6.80-6.87 (in, 3H), 7.03 (2 doublets, J=2Hz, 1H), 7.30 J=9Hz, 1H-).

WO 99/06397 WO 9906397PCT/US98/1 5479 00 -108- Examp~eAa trans, trans-2-(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-!yfl- 1 -(N.N-diLn Nl butyvIaminoca rbonyvlethvl)pyrrolidine-3-carboxylic acid The title compound was prepared using the procedures described 00 in Example 1. m.p. 123-125 0 C. 1 H NMR (CDCI3, 300 MHz) 8 0.79 (tg C\ J=7Hz, 311), 0.85 J=7Hz, 3H), 1.00-1.50 (in, 8H), 2.74 J=l3Hz, III), 2.90-3.09 (in, 4H), 3.23-3.50 (in, 3H), 3.38 J=l3Hz, 1H), 3.52-3.62 0 00 J=8Hz, 111), 6.81-6.89 (in, 3H), 7.03 J=2Hz, 1H1), 7.30 J=9 Hz, 211). MS (DCI/NH 3 m/e 511 Anal calcd for C 29

H

3 8N 2 06: C, 68.21; H, 7.50; N, 5.49. Found: C, 68.07; H, 7.47;, N, 5.40.

Examgle 44 trans. trans- 2 -(4-Methoxyohenyl)-4-( 1.3-benzodioxol-5-fl)- 1 .Nd iethyl am in ocgrbonylmethfl-12rrol idi e-3-ca rboXa ic acid The title compound was prepared using the procedures described in Example 1. m.p. 132-134 OC. 1 H NMR (CDCI3, 300 MHz) 8 0.98 (t, J=7Hz, 3H), 1.06 J=7Hz, 3H), 2.78 J=13 Hz, 1H), 2.95-3.20 (mn, 4H), 3.30-3.50 (in, 4H), 3.55-3.65 (in, 1H), 3.76 J=12 Hz, 1H1), 3.79 3H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (d, J=2Hz, 1H), 7.32 J=9Hz, 2H1).

Example trans, trans-2-(4-Methoxyphenl)-4-( 1.3-benzodioxol-5-y)- 1 -(N-rn ethyl-Nohenylam inocarbonylmethyl-rrolidine-3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. 1 H NMR (CD 3 OD, 300 MHz) 8 2.75- 2.85 (in, 2H), 3.05-3.13 (in, 1H), 3.18 3H), 3.40-3.58 (in, 2H), 3.78 3H), 3.88 J=l2Hz, 1H), 5.92 2H), 6.72 J=8Hz, 11H), 6.75- 6.85 (mn, 3H), 7.00-7.12 (in, 5H), 7.82-7.92 (in, 3H).

Examgle 46 trans, trans-2-(4-MethoxylhelYF)-4-( 1.3-benzodioxol-5-yfl)-1 -(N-methyl-Ncyclohexylaminocarbonylmethyl')-Yrrolidile3-carboxylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NM.K.. 1H.. NMR (CD3O0D. 300 MHz) 8 1.00-1.85 (in, 10H), 2.72 and 2.78 (2 WO "/06397 WO 9906397PCT/US98/1 5479 00 -109singlets, 2.75-2.82 (2 doublets, J=l2Hz, 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 S(2 singlets, 3H), 5.92 6.72 (2 doublets, J=BHz, 1H), 6.82-6.88 (in, 3H1), 7.02 (2 doublets, J=2Hz, 11H), 7.30-7.40 (2 doublets, J=9Hz, 00 2H).

Eaml~ie 4 Ntrans, trans-2-(4-MethXo~henyl')-4-( 1.3-benzodioxol-5-y)- 1 .N-di (n- 00 prprylaminocarbonylmethyl)-Dyrroldine-3carboxylic acid The title compound was prepared using the-procedures described in Example 1. in.p. 170-172 00. I'H NMR (CDCI3, 300 MHz) 8 0.69 (t, J=7Hz, 3H), 0.85 J=7Hz, 3H), 1.20-1.55 (in, 4H), 2.72 J=l3Hz, 1H), 2.90-3.10 (in, 4H), 3.25-3.47 (in, 4H), 3.35-3.62 (in, 3.72 J=9Hz, 111), 3.79 3H), 5.94 2H), 6.72 d, J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 J=2Hz, 11H), 7.30 J=9Hz, 2H).

Examl~l 4 trans. trans 2(4MehxYlhenYl- 4 -(l.3-benzodioxol-5-yi')-1 -(N-methyl-NisobutylamninocarbonylmethyflD-yrrolidile-3-carbocylic acid The title compound was prepared as an amorphous solid using the procedures described in Example 1. Rotational isomers were seen in the NMR. IIH NMR (CD 3 OD, 300 MFz) 8 0.65-0.85 (4 doublets, J=7Hz, 6H), 1.75-1.95 (in, 1H), 2.80 and 2.90 (2 singlets, 3H), 2.90-3.10 (in, 4H), 3.10-3.65 (mn, 3.74 9S, 3H), 3.81 and 3,88 (2 doublets, J=l OHz, I H), 5.93 2H), 6.72 J=8Hz, 1H), 6.80-6.90 (in, 3H), 7.02 (2 doublets, J=2Hz, 1IH), 7.80-7.90 (2 doublets, J=9Hz, 2H).

Examgle 49 Alternate Preration of Ethyl 2(4methoxybenzoyl-4nitroiethl 3 Exam ole 49A E--2-(3.4-MethylenedioXYphenfl)l 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 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 iniol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while WO 99/06397 PCT/US98/15479 00 -110maintaining the temperature between 10-15 The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for c minutes upon completion of the addition, and the mixture was then Sdiluted with ice-water (-350 mL) maintaining the temperature below OC, until solution was achieved. The resultant solution was poured in a 00 narrow stream (such that it just failed to break into drops) into a S rapidly stirred solution of 36% hydrochloric acid (100 mL) in water 0 (150 mL). A yellow solid precipitated (nitrostyrene), and this was oo 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 C- 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 3 m/e 194 (M+H) 211 (M+H+NH3) Example 49B Ethyl 2.(4-methoxvohenv)oxo-4-nitro- 3 3 .4-methvlenedioxvphenvl)butvrate To a stirred solution of the nitrostyrene resulting from Example 49A (14.17 g, 73.34 mmol, 1.2 eq) in a mixture of propan-2-ol (75 mL) and tetrahydrofuran (175 mL) at room temperature was added successively a solution of ethyl (4-methoxybenzoyl)acetate (11.5 g, 51.7 mmol) in THF (50 mL) followed by 1,8-diazabicyclo[5,4,0]undec-7ene (DBU) (0.45 mL, 3.0 mmol, 0.05 eq). The resultant mixture was stirred at room temperature for 1 hour, then additional DBU (0.45 mL, 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 2 5 ethyl acetate-hexanes as the product eluted. The solvents were removed in vacuo to yield the nitroketoester (19.36 g, 7 6 as a viscous oil. Diastereomers were seen in the NMR.

1H NMR (300 MHz, CDC3l,) 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, WO 99/06397 PCT/US98/15479 00-11 in),3.80 3.78 (3H, 1.19 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz), MS (DCI/NH3) m/e 416 433 (M+H+NH3)+.

00 trans, trans-2- Meth oxypheflyl)-4- (1 ben zodioxol- 5-yi)- 1 (t- __butylogycarbonylm ethyl~)-pyrrolid i ne3-ca rbo(ylic acid To a stirred solution of the compound resulting from Example 1IC N (100 mg, 0.27 mmol) in acetonitrile (2 ml-) was added successively 00 diisopropylethylamine (70 0.40 mmol, 1.5 eq) and t-butyl ci bromoacetate (48 ltL, 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% wlw sodium hydroxide (300 mng, 3.75mmol) in water. The mixture was stirred 2 hours; then the volatiles were 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 giL), and then extracted with ethyl acetate The combined organic extracts were dried (Na 2 SO4), filtered, and concentrated to yield the title compound (74 mng, 60%) as a white solid.

I H NMR (300 MHz, CDCI3) 8 7.36 (2H, d, J=8Hz), 7.13 (1 H, d, J=3Hz), 6.90 (OH, dt, J=3Hz, 8Hz), 6.88 (2H, d, J=BHz)., 6.76 (1H, d, J=8Hz), 5.96 (2H, 3.96 (1H, d, J=9Hz), 3.81 (3H, 3.58 (1H, ddd, J=12, lOHz,3Hz), 3.52 (1H, dd, J=9Hz,3Hz), 3.32 (1H, d, J=l7Hz), 3.08 (1H, t, J=lOHz), 2.92 (OH, dd, J=9Hz,7Hz), 2.83 (1H, d, J=l7Hz). MS (DCI/NH 3 W/e 456 Anal calc for C 29 H29NO7 0.3 H20: C, 65.07; H, 6.48; N, 3.04. Found: C, 65.02; H, 6.42; N, 2.93.

trans. trans-2-(4-MethoxVlhenyl- 4 (1 -n anhthyfl- 1 -(N-methyl-N- Urooyflam inoca rbonylm ethyl)-gyrro lid in -3-carboxlic acid' The title compound was prepared by the procedures described in Examples 1 and 49 substituting naphthalene- 1-carboxaldehYde for piperonyl in Example 49A. Rotational isomers are seen in the NMR. 1

H

NMR (300 MHz, CDC13) 8 8.29 (1H, bd, J=8Hz), 7.86 (2H, d, J=BHz),7.75 (1H, d, J=8Hz), 7.49 (3H, in), 7.34 (2H, dd, J=3Hz,9Hz), 6.83 (2H, dd, J=gHz,2Hz), 4.50 in), 3.94 (1H, dd, J=9Hz,2Hz), 3.78 (3H, 3.65 WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -112- S(1H, in), 3.49 (11H, d, J=l4Hz), 3.40-2.93 (5H, in), 2.91, 2.83 (3H, 1.48 (2H, sept, J=7Hz), 0.83, 0.77 (3H, t, J=7Hz).- MS (DCI/NH3) W/e 461 Anal calcd for C 29

H

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

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

00 trans. trans-2-(4-Methox oyl)-4-(2.3-dihydroblzofuraf5Yl)-1 -(N-methyl-N- N propyflaminocarbonylmethyfl)-pyrrolidine-3-carboxylic acid 00 Examl 2A 2 .3-Dihydrobenzofurafl-5-ca rboxaldehyde To a stirred solution of ctct-dichloromethyl methyl ether (2.15 g, 19 inmol, 1.35 eq) in methylene chloride (30 mL) at -40 00 was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzof uranl (1.68 g, 14 inmol) in CH 2

CI

2 mL) maintaining the temperature at or below -35 OC. The mixture was warmed to 0 CC, stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 00 at 0.3 mm Hg.

trans, trans-2- (4-M eth oxyghe nl)-~4 (2.3 dihydroben zof uran YI)- methyl -N g2ro pyl) am i nocarbonylm ethyl)-Dyrroli dinle- 3ca rboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the compound resulting from Example 52A for piperonal in Example 49A. Rotational isomers are seen in the NMR. IH NMR (300 MHz, CDCI3) 6 7.33 (1H, 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 (1H, 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 (DCI/NH3) mWe 453 Anal caic for C 26

H

3 2

N

2 O5 0.25 H 2 0: C, 68.33; H, 7.17; N, 6.13. Found: C, 68.60; H, 6.88; N, 5.80.

WO 99/06397 WO 9906397PCTIUS98/I 5479 00 -113- Exam trans. trans-2.4-Bis (4-m eth oXyphenl)f- 1 (N-m eth yl-N -ropyl~)am in oca rbonylm ethyl)c-I Dyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in 00 Examples 1 and 49 substituting 4.methoxybenzaldehyde for piperonal in C\ Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) 8 7.37 (2H, d, J=7.5 Hz), 7.32 (2H, d, J=7.5 Hz), 6.86 (4H, in), N- 3.83 (1 H, in), 3.81 (3H, 3.79 (3H, 3.64 (1IH, in), 3.48-2.97 (6H, in), 00 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/NH3) mWe 441 Anal calc for C 25 BUN205 -0.5 H20: C, 66.80; H, 7.40; N, 6.23. Found: C, 67.15; H, 7.31; N, 6.00.

Examlle 54 trans, trans-2-(4-Metho Dphefl)l'4(3.4-dimethoxvhenyIl)- -(N-methyl-N- 12r02YI~am inocarbonyl methyl)-pyrro lid in e- 3-carboXylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-diinethoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1H NMR (300 MHz, CDCI3) 8 7.33 (2H, d, J=7.5 Hz), 7.07 (1 H, d, J=2.0 Hz), 6.98 (1 H, in), 6.85 (1 H, d, 7.5 Hz), 6.82 (2H, d, 7.5 Hz), 3.91 (3H, 3.86 (3H, 3.83 (1 H, in), 3.79 (3H, 3.64 (1 H, in), 3.50-2.95 (6H, in), 2.87 (1 H, in), 2.85, 2.83 (3H, 1.45 (2H, mn), 0.84, 0.74 (3H, t, J=7.5 Hz). MS (DCIINH3) Wne 471 Anal caic for C 2 6H34N2O6 0.5 H20: C, 65.12; H, 7.36; N, 5.84. Found: C, 65.22; H, 7.27; N, 5.59.

Examle trans. trans-2-(4-MethoXyphenvi)-4-( 3 -m ethoxyphenyl)- 1 -(N-methyl-Np ropyl~ainocarboflylm ethyl-pyrro lid i e-3-carbocyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-methoxybenzaldehyde for piperonal in Example 49A. Rotational isomers are seen in the NMR. 1 H NMR (300 MHz, CDCI3) 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 (1 H, in), 3.83 (1 H, in), 3.81 3.79 (3H, 3.64 (1 H, in), 3.48-2.97 (6H, in), 2.87, 2.83 (3H, 2.85 (1 H, in), 1.45 (2H, in), 0.84, 0.74 t, J=7.5 Hz). MS (DCI/NH3) m/e 441 (M+H) 4 WO 99/06397 WO 9906397PCTIUS98II 5479 00 -114- SAnal caic for C 25

H

32

N

2 0 5 0.5 H 2 0: C, 66.80; H, 7.40; N, 6.23. Found: C, 66.76; H, 7.36; N, 6.05.

OC) trans. trans-2-(4-Methoxyohenyl-4-(2-nahthyl)- 1 -(N-methyl-Nprogyflam inoca rbonylmethyl)-pyrro lid ine-3-carboxylic acid The title compound was prepared by the procedures described in ci Examples 1 and 49 substituting naphthylene-2-carboxaldehyde for 00 Spiperonal in Example 49A. Rotational isomers are seen in the NMR. 1H SNMR (300 MHz, CDCI 3 8 7.82 in), 7.69 (1H, 7.47 (2H, in), 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 (3H1, 3.57 (1H, mn), 3.52-2.97 (6H, in), 2.93, 2.85 2.90 (1H, in), 1.52 (2H1, in), 0.86, 0.76 (3H, t, J=7.5 Hz). MS (DCI/NH 3 m/e 461 Anal calc for C 28

H

32

N

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

trans. trans-2-(4-Methoxyghenyl)-4-( 1.3-ben zodioxol-S-yfl- 1 -(2-(ethlsulfinyl)ethyl)ip2yrrolidine-3-carboxylic acid To the compound resulting from Example 1C (100 mg, 0.27 minol) and 2-chloroethyl ethyl sulfide (67.5 mg, 0.5 minol, 2 equivalents) dissolved in 6 mL of acetonitrile was added 10 mg of KI and 0.5 mL of diisopropylethylamine. The mixture was refluxed for 4 hours and then concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel eluting with 4:1 hexane-ethyl acetate to afford 93 mg of the ethylthioethyl compound.

To the sulfide (90 mng, 0.2 inmol) dissolved in 5 mL of CH- 2

CI

2 in an ice bath was added 68 mng of 3-chlo rope roxybe nzoi c 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-2CI 2 to afford the sulfoxide (62 mng, The ethyl ester was hydrolyzed by the procedure described in Fvyamnp ID to afford the title compound as a diastereomeric mixture.

WO 99/06397 PCT/US98/15479 0O9/690CTU9/57 00 -115- S m.p. 61-63 0 C. MS (DCI/NH3) mle 446 1 H NMR (CDCI3, 300 MHz) 8 1.25, 1.32 J=9Hz, 2.45-2.75 (in, 4H), 2.84-2.96 (in, 3H), 3.02- 3.08 (mn, 1H), 3.32, 3.36 J=3Hz, 1H), 3.47-3.58 (in, 2H1), 3.65, 3.68 (d, 11H), 3.76, 3.80 3H), 5.94 2H), 6.72 J=7.5Hz, 11H), 3.84- 00 3.89 (mn, 3H), 7.02 J=6Hz, 1H), 7.30, 7.34 J=7.5Hz, 2H).

Examle58 00toans. trang-2-(4-MehoxY=heflvl- 4 3-benzodioxol-5-y)-1 (isogronylsulfonylam ino)ethyfl)-Drrolidifle-3-ca rboxylic acid To 2-bromoethylamifle hydrobromide (1 mnl'61) suspended in anhydrous

CH

3 CN was added 1 equivalent of EI3N. The mixture was stirred for 30 minutes and then 1 equivalent of isopropyl sulfonyl chloride and 1 equivalent of Et 3 N were added. The resulting mixture was stirred for 2 hours at room temperature and then added to a solution of the compound resulting from Example 1C (185 mg, 0.5 inmol) in 3 mL of CH3CN. The mixture was warmed at 50-60 00 for 2 hours, cooled to room temperature, treated with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried and concentrated in vacuo. The residue obtained was 0 chroinatographed on silica gel eluting with 3:2 hexane-EtOAc to give 195 mg (750/) of the ethyl ester. The ethyl ester (160 ing, 0.31 minol) was hydrolyzed by the procedure described in Example 1ID to afford the title compound (133 mg, m.p. 94-96 OC. I H NMR (CD 3 OD, 300 MHz) 8 1.26 J=6Hz, 1.97 I1H), 2.38 (in, 1 2.77 (mi, 1 2.88 J=9Hz, 1 3.04 (in, I1H), 3.14 J=7.5Hz, 211), 3.35 (mn, 2H), 3.46 (in, 1 3.58 (mn, 1 3.78 5.92 2H1), 6.74 J=9Hz, 1 6.86 (dd, J=9Hz,3Hz, I1H), 6.92 J=9Hz, 2H), 7.00 J=3Hz, I1H), 7.36 J=9Hz, 2H). MS (DCI/NH3) Wne Fxampile trans. trans 2(-Methoxyphenfl)- 4 3-ben-zodioxol-5-yl)-l--(2- (isobutoxy)ethyl- 12yrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Example 1 D from the compound resulting from Example 1 C and 2- (isobutoxy) ethyl bromide. in.p. 68-70 00. 1 H NMR (CDC13. 300 MHz) 8 0.88 J=6Hz, 6H), 1.82 (quintet, J=6Hz, 2.22 (in, 2.72-2.79 WO "/06397 PCT/US98/15479 00 (in,11H), 2.86-2.95 (in, 2H), 3.13 J=6Hz, 2H), 3.45-3.56 (in, 4H), 3.68 Ni J=9Hz, 1 3.79 3H), 5.94 2H), 6.72 J=7.5Hz, 1 6.85 (dd, J=9Hz, 7.5 Hz, 3H), 7.08 1 7.34 J=9Hz, 2H). MS (DCI/NH 3 m/e 00 442 trans. trans-2-(4-M ethoxvohenyfl-4-( 1.3-benzodioxol-5-yfl-1 -(butvlsulfonyl)- 00 gyrrolidine-3-carboxylic acid To 100 mg (0.271 mmol) of the compound resulting from Example I C dissolved in 10 mL of THF was added 1-butaflesulfonyl 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 ing, 0.244 iniol) was dissolved in 1 mL of EtOHI and a solution of 100 ing 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 3 solution was washed with ether to remove any unhydrolyzed trans-cis isomer. The aqueous solution was acidified to pH-6 with acetic acid and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the pure title compound (60 ing, 53%) as a white solid. m.p. 67-69 OC. I H NMR (CDC13, 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=l2Hz, 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, 2H), 7.35 J=9Hz, 2H). MS (DCI/NH3) m/e 462 trans. trans-2-(4-MethoxvphenYfl-4-(l .3-benzodioxol-5-y)- 1 -(2-(N-methyl-Nisprpylcarbonvipmino)ethyl)-ovrrolidine- 3 carbo(Yic acid WO 99/06397 PCT/US98/15479 00 -117- Example 61 A Strans. trans-2-(4-MethoxyDhenvl-4-(1.3-benzodioxol-5-vl)-1 -(2-bromoethyl)oyrrolidine-3-carboxylic acid ethyl ester To the mixture of cis,trans and trans,trans pyrrolidines resulting oo 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

N

0 solvents were removed in vacuo. The residue was taken up in EtOAc and S washed sequentially with water and brine, dried and concentrated under c reduced pressure. The crude product was purified, by flash chromatography on silica gel eluting with 4:1 hexane-EtOAc to give 470 mg of the title product.

Example 61 B pyrrolidine-3-carboxylic 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 OC 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-Methoxvhenyl-4- 1.3-benzodioxol-5-vyl)-1 -(2-(N-methyl-Nisobutyrylamino)ethylv-pyrrolidine-3-carboxylic acid To the compound resulting from Example 61B (-150 mg) dissolved in 5 mL of 1,2-dichloroethane was added 0.3 mL of diisopropylethylamine. The solution was cooled to -40 isobutyryl chloride (0.17 mL) was added, the bath was removed, and the solution was allowed to warm to ambient temperature and stirred for 15 hours.

The solvent was removed in vacuo; the residue was taken up in EtOAc and washed sequentially with 1:1 sodium bicarbonate solution/water and brine, dried and concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with a gradient 1:1 EtOAchexanes going to EtOAc and finally using 10% MeOH-EtOAc.

WO "/06397 PCT/US98/15479 00 The ester was dissolved in 1.5 mL of EtOH; 0.75 mL of a 17% Cl aqueous NaCH solution was added, and the resultant mixture was stirred at ambient temperature for 3 hours. The solvents were removed in 00 vacua; the residue was taken up in water and washed with ether. The Saqueous 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 Na2SO4. The solvents were removed in vacuo to provide 82 00 mg of the title compound as a white foam. Rotamers were seen in the NMR. I H NMR (CDC13, 300 MHz) of the major rotamer 8 1.06 3H1, 3 J=lOHz), 1.12 3H, J=lOHz), 2.15 (in, 1H), 2.5-1.0 (in, 2.91 3H-), 3.32 (in, 2H), 3.50 (in, 2H), 3.65 (in, 2H), 3.77 3H), 5.92 2H), 6.73 1H, J=8H1z), 6.75-6.9 (mn, 4H), 6.96 1H, J=2Hz), 7.29 (mn, 1H). MS

(DCI/NH

3 mlz 469 Analysis calcd for C 26 H1 32

N

2

O

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

Example 62 trans, trans-2-(4-Methoxy~henyl)-4-( 1.3-benzod ioxol-5-fl)- 1 -(2-(N-meth lN- 2rogionylam ino~ethyl)-o2yrrolidine-3-ca rboxylic acid The title compound was prepared by the procedures described in 0 Example 61 substituting propionyl chloride for isobutyryl chloride in Example 61C. 1 H NMR (CDCI 3 300 MHz) of the major rotamer 8 1.13 (t, 3H, J=8H1z), 2.19 (in, 1H), 2.30 (in, 2H), 2.65-3.0 (in, 3H), 2.85 3H), 3.25-3.4 (in, 2H), 3.5-3.7 (in, 3H), 3.79 3H1), 5.92 6.74 1H, J=BHz), 6.75-6.9 (in, 7.00 (bd s, 1H), 7.29 (bd s, 1H). MS (DCIINH 3 m/z 455 Analysis calcd for C 2 5H 3 aN 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.

Examgle6.

trans, trans-2-(4-Methoxylhenyfl-4- (1 .3-benzodioxol-5-yl)-1 -(N-methyl-Nbenzylam inocarbonylnethy)-yrrolidile-3-carboxylic -acid Using the procedures described in Example 1 the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) of the major rotainer 2.79 (s, 3H), 2.8-3.2 (in, 2H), 3.48 (in, 2H), 3.61 (in, 2H), 3.77 3H), 3.78 (mn, 1H), 4.3-4.5 (mn, 2H), 5.95 2H, J=2Hz), 6.7-6.9 (in, 4H), 7.00 (in, 1H), 7.15-7.35 (in, 7H). MS (FAB/NBA) m/z 503 Anal calcd for

C

29

H-

30

N

2 06 0.5 H20: C, 68.36; H,5.74; N, 5.50. Found: C,68.41; H, 5.74; N, 5.36 WO 99/06397 PCTIUS98/15479 00 Exam&-O trans. trans-2-(4-Methoy~henl)-4-( 1.3-benzodioxol-5-yl)-l1-(N-ethyl-Nbutylaminocarbonylmethyl-rDyrrolidile-3-carboXylic- acid 00 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, J=7Hz), 1.27 (in, 2H), 1.45 (in, 2H), 2.8-3.6 (in, 00 I 3.79 3.80 (in, I1H), 5.92 (bd s, 2H),6.5(,HJBz,.8 1H, J=8Hz), 6.92 2H, J=8Hz), 7.03 1H), 7.33 1H, J=8Hz). MVS N1 (DCI/NH3) m/z 483 Anal calcd for C 2 7 H34N206 -0.5 HOAc: C, 65.61; H,7.08; N, 5.46. Found: C,65.51; H, 6.70; N, 5.66.- Examlile 6 trans. trans-2-(4-Methoxvrhenyl)-4- (1 .3-benzodioxol-5-yfl)- -(N-methyl-N-22 di tygoy)aioabnl e l-~roiie3croWi acid Using the procedures described in Example 1 the title compound was prepared. IH NMR (CDCI3, 300 MHz) of the major rotamer 8 0.90 (s, 9H), 2.8-3.1 (in, 4H), 2.94 3H), 3.3-3.5 (in, 3H), 3.61 (in, 1H), 3.80 (s, 3H), 3.82 (in, 1H), 5.94 (bd s, 2H), 6.74 1H, J=8Hz), 6.86 2H, J=8Hz), 63B7 (in, 1H), 7.03 1H, J=21-z), 7.33 2H, J=8Hz). MS (DCI/NH3) m/z 483 F~xample66 trans. trpns-2-(4-Methoxyhenyl 1.3-benzodioxol-5-y- 1 (Nm ethyl-Nbutylsulfonylamino~ethyflO1yrrolidine-3-carboxylic acid To the compound resulting from Example 61B (60 mg, 0.13 inmol) dissolved in 5 mL of CH 3 CN was added 0.2 mL of Et 3 N and 22 mng (0.143 minol, 1.1 equivalents) of 1-butanesulfonyl chloride. The mixture was stirred for I hour at room temperature and then concentrated in vacuo.

The crude product was purified by column chromatography on silica gel eluting with 1:1 EtOAc-hexane to yield 64 mng of the ester. Ester hydrolysis by the procedure described in Example 1 D afforded the title compound. m.p. 64-66 0 C. H NMR (CDCI3. 300 MHz) 8 0.92 3H), 1.39 (hexad, J=7.5Hz, 2H), 1.68-1.76 (in, 2H), 2.16-2.25 (mn, 1H), 352.72 3H), 2.75-2.92 (in, 5H), 3.12-3.20 (in, 1H), 3.25-3.34 (mn, 1H), 3.46-3.55 (mn, 2H), 3.65 J=9Hz, 1H), 3.78 3H), 5.53 2H), 6.72 (d, WO 99/06397 PCT/US98/15479 00 -120- 1 6.82 (dd, J=7.5Hz,3Hz, 1 6.86 J=9Hz, 2H), 7.02 (d, J=3Hz, 1 7.34 J=9Hz, 2H). MS (DCI/NH3) m/e 519 Examl 6 00trans. trans-2-(4- MethgyMhenl)l4-(j 1 3-benzodioxol-5-vFI- 1 N-methyl-N- D2ropylsu Ifonylam ino)ethyl)-pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in 00 Example 66 substituting 1-propanesulfonyl chloride for 1butanesulfonyl chloride. m.p. 69-70 OC. 1H NMR (CDCI3. 300 MHz) 8 1.02 J=7.5Hz, 3H), 1.78 (hexad, J=7.5Hz, 2H), 2.18-226 (in, 1H), 2.72 (s, 3H), 2.75-2.95 (in, 6H), 3.13-3.22 (in, 1H), 3.25-3.35 (in, 1H), 3.47-3.58 (in, 2H), 3.66 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.74 1H), 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) in/e 505 Example 6 trans, trans-2-(4-Methoxy12henyl)-4-( 1.3-benzodioxol-5-yfl-l (Drooylsulfoflyl)ethyfl-Oyrrolidile3-carboxylic acid To 1-propanethiol (3.5 g, 46.05 mmol) dissolved in 10 mL of anhydrous THF was added 632 mg (26.32 inmol) of NaH in portions under a nitrogen atmosphere. The mixture was heated at 60-70 OC for 1 hours.

To this mixture was added the compound resulting from Example 61A (180 mg, 0.38 minol) in 2 mL THF. Heating was continued at 60-70 OC 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 mg (0.36 inmol) of the sulfide and 93 mg (0.8 minol) of N-methylmorpholine N-oxide (NMO) in a mixture of 20 mL of acetone and 5 mL of H20 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 vacua. Flash chromatography afforded 177 mng of the ethyl ester which was hydrolyzed by the procedures described in Example 1 D to afford the title WO 99/06397 PPr/S98/1 5479 00 S-121compound. m.p. 73-75 'H NMR (CDCI3, 300 MHz) 6 1.04 C 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/NH3) S m/e 476 (M+H) 0 00 Example 69 S trans.trans-2-(4-Methoxvyhenvl-4-(1.3-benzodioxol-5-vly-1-N-(trans-5-methylhex- 2-enyl)-Dvrrolidine-3-carboxylic lcid Example 69A trans-5-Methvlhex-2-enoic acid ethyl ester Oil dispersion sodium hydride (0.85 g) was washed with hexanes and suspended in THF (20 mL), and the mixture was cooled in an ice bath to 0 Diisopropyl(ethoxycarbonylmethyl) phosphonate (5.0 mL) was added slowly and the mixture stirred for 20 minutes at 0 *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 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 OC 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 e :!int and w qhings. were combined, dried, and evaported to give a WO 99/06397 PCT/US98/15479 00 122- S colorless oil which was purified by flash chromatography on silica gel Ni eluting with 25% EtOAc-hexanes. The title compound was isolated as a colorless oil (1.25 g).

00 trans-i -Bromo-5-melthylhex-2-ene The compound resulting from Example 69B (1.0 g) was dissolved in 00 diethyl ether and cooled to 0 0 C in an ice bath. Phosphorus tribromide 0 (2.5 g, 0.87 mL) was added dropwise and the solution stirred at 0 0 IC 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).

trans. trans-2- (4-Methoxyo~henyl)-4-( 1.3.benzodioxol-5-fl)- 1 2-enyl)-oyrrolidine-3-crboxylic acid The title compound was synthesized using the methods detailed in Example 1 D but substituting the compound resulting from Example 69C for N-propyl bromoacetamide. 1 H NMR (CDC13, 300 MHz) 8 0.84 6H, J=8Hz), 1.57 (heptet, 1H, J=8Hz), 1.87 2H, J=6Hz), 2.60 (dd, 1H, J=8Hz,l4Hz), 2.86 1H, J=lOHz), 2.96 (dd, 1H-, J=8Hz,lOHz), 3.20 (dd, 1H, J= 5Hz,l4Hz), 3.29 (dd, IH, J=3Hz,lOHz), 3.50 (in, 1H), 3.70 1H, J=lOHz), 3.78 3H), 5.47 (in, 2H), 5.93 2H), 6.71 1H, J=BHz), 6.83 3H, J=9Hz), 7.05 1H), 7.32 2H, J=9Hz). MS (DCI/NH3) mWe 438 Anal calcd for C 26

H

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

trans. trans-2- (4-Methoxygh efyl)- 4- 3-ben zod ioxol -5 -yl) 1 N -(tra dim eth ylhex-2-eyl)-pyrro id i ne3-ca rbo xyl ic acid The title compound was prepared by the procedures described in Example 69 but substituting 4-methyl-2-pefltaflone for isovaleraldehyde in Example 69A, which gave -7:1 mixture of trans/cis olef ins. The crude product was purified by preparative HPLC (Vydac 4iC18) eluting with a 10-70% gradient of CH 3 CN in 0.1% TFA. The uj~s're- kinii.ar tn nivethe product (and its WO 99/06397 PCT/US98/15479 00 8 -123diastereomer) as a white solid. 1 H 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, oo 1H), 7.45 3H, J=8Hz). MS (DCI/NH 3 m/e 438 Anal calcd for

C

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

00 Example 71 trans. trans-2-(4-Methoxvohenvl)-4-(1.3-benzodioxol-5-vl)-1 heDtylcarbonvlmethyl-vyrrolidine-3-carboxylic acid Example 71 A 1-Chloro-3-proDyl-2-hexanone To 2-propylpentanoic acid (156.6 i 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 gL, 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 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 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 gL, 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-methoxyDhenvl-4-(1.3-benzodioxol-5-vil-1-( 4 heDtvlcarbonvlmethylf-Dvrrolidine-3-carboxvlate To the compound resulting from Example 71A (1.00 mmol, maximum theoretical yield) was added a solution of the trans,trans WO 99/06397 PC/US98/1 5479 00 S-124ethyl carboxylate from Example 1C (295 mg, 0.80 mmol as a 50 solution in toluene), diisopropylethylamine (700 gL, 4.00 mmol) and acetonitrile (4 mL). To the resulting solution was added sodium iodide (12 mg, 10 mole and the reaction mixture was stirred 18 hours 00 under a nitrogen atmosphere at ambient temperature. Additional sodium S iodide (24 mg, 20 mole and acetonitrile (4 mL) were added, and the O reaction mixture was heated at 45-50 °C with stirring for 18 hours.

oo The reaction mixture was concentrated under reduced pressure, and the S residue was chromatographed on silica gel eluting with 1:9 ethyl C acetate-hexane to give 237 mg of the title -compound as a yellow oil.

Examole 71C trans, trans-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-vl-1 heDtylcarbonvlmethvl-Dpyrrolidine-3-carboxylic acid To the compound resulting from Example 71B (231 mg, 0.4532 mmol) dissolved in ethanol (10 mL) was added a solution of lithium hydroxide (38 mg, 0.9065 mmol) in water (2.5 mL). The solution was stirred for 18 hours under a nitrogen atmosphere, additional lithium hydroxide (19 mg, 0.4532 mmol) in water (0.5 mL) was added, and stirring was continued 24 hours. The reaction mixture was concentrated under reduced pressure to remove the ethanol, and the aqueous residue was diluted with water (45 mL) and washed with ether mL). The aqueous layer was neutralized with 1 N hydrochloric acid to cloudiness and then 10% aqueous citric acid was added to adjust the 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) 8 0.73-0.97 6H), 1.03-1.33 6H), 1.36-1.58 2H), 2.46 1H), 2.80-2.98 3H), 3.38-3.64 3H), 3.75-3.90 1H), 3.79 3H), 5.94 2H), 6.75 1H), 6.86 2H), 6.92 1H), 7.12 1H), 7.32 2H). MS (FAB) m/e 482 Anal calcd for C 28

H

3 5

NO

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

WO 99/06397 PCT/US98/15479 00 -125- Exampl 2 c-i trans, trans-2-(4-Methoyphenl)f-4-( 1.3-benzodioxol-5-yl)- 1 -(valerylmethyl pyrarolidine-3-carboxylic acid 00 Example 72A 1 -Chloro-2-hexanofle Using the procedure described in Example 71A and substituting 00 pentanoic acid for 2-propylpentanoic acid afforded the title compound as an oil which was used in the next step without further purification.

Examgle 72 trans. trans-Ethyl 2-(4-methoxyphenl)l-4-(l .3-benzodioxole-5-yl)-l (valerylmethy1)-yrrolidife3carboxylat~e Substituting the compound resulting from Example 72A for 1chiloro.3-prpyl-2-he xanone 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.

Example 72C trans, trans-2-(4-Methoxyghenl)- 4 (valerylmethyflpyrrolidine3carboxylic acid By substituting the compound resulting from Example 72B for trans, tra ns- Ethyl 2-(4-methoxyphenyl)- 4 ,3-benzodioxol-5-yl)-l heptylcarbonyl methyl) -pyrrol idin e 3 carboxyl ate and using the procedure described in Example 71C, except only one solution of lithium hydroxide (81.5 mg, 1.942 mmol) in water (3.5 mL) was added followed by stirring for 18 hours, the title compound 130 mg was obtained as an off white powder. 1 H NMR (CDCI3, 300 MHz) 8 0.87 (t, 3H), 1.26 (in, 2H), 1.49 (in, 2H), 2.37 (in, 2H), 2.79-2.98 (mn, 3H), 3.31- 3.49 (in, 2H), 3.56 (in, 1 3.77, 3.79 4H1), 5.94 2H), 6.75 1 H), 6.81-6.93 (mn, 3H), 7.09 (K 1H), 7.33 2H). MS (FAB) in/e 440 Anal. calcd for C 2 rH29NO6: C, 68.32; H, 6.65; N, 3.19. Found: 67.95: H, 6.64; N, 3.05.

WO 99/06397 PCTIUS98/15479 00 -126- Examl~le 73 trans. trans-2-(4-Methoxvohelyfl-4 4 1 .3-benzodioxol.5-yl)-1 4dim eth oXyben Zyl)N-m ethla m noca rbgflyl methyl) yrroidi ne 3 arboxyl ic acid 00 Examl~le 7A trans.trans- and cis trans2-(4Methoxyheyl4-( 1 .3-ben 00 1 3 -4-di methogxyben zyl) am i oga rbonl m ethyl) Pyrrol idi ne- 3 carboxylic acid ethyl ester Using the procedure of Example 1D, paragraph 1, substituting 3,4dimethoxybelzyl bromoacetamide for dipropyl bromoacetamide, the desired product mixture was obtained as a white foam in 81% yield.

Examlle 73B 1 I A A~4~ INI..A-1 'A-han-7nrjjnYnt-S-.

i trans.trafls- and c~~rasU wisiwuu yb)-i (N.(3.4-dimethoxybenzyfl-N- The resultant product from Example 73A (220 mg, 0.404 mmol) was dissolved in 2 mL dry THE and added dropwise to a stirred, cooled (0 00) suspension of sodium hydride (23 mg of a 60% by weight mineral oil suspension, 16.5 mg, 0.69 mmol) in 0.2 mL THF, under an argon atmosphere. The resulting mixture was stirred at 0 OC for 1 hour, then methyl iodide (28 p.L, 64 mg, 0.45 mmol) was added. The reaction mixture was stirred at 0 0 IC for 45 minutes. TLC (Et2O) indicated incomplete reaction. An additional portion of methyl iodide (28 4iL, 64 mg, 0.45 mmol) and dry 1 ,3-dimethyI-3,4,5,6-tetrahydro- 2(1 H)pyrimidinone (50 glL, 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. 1H NMR (COCl 3 300 MHz) 8 2.79 and 2.81 for the N-CH3 signals. MS m/z 591 WO 99/06397 PCT/US98/15479 00 -127- Exgample 73C tranis. trans- 2- (A4-Methoxypheflyfl-4 1.3- be nzo-di o xol-5-Yb)- 1 (3.4dimethoxybenzyl)-Nmethylami nocarbofylm ethyl) pyrroi di ne- 3 00 To the resultant compound from Example 73B (98 mg, 0.17 mmol) dissolved in 1 mL EtCH and cooled to 0 0 C was added a solution of lithium hydroxide monohydroxide (17 mg, 0.41 mmol) in 0.5 mL H 2 0. The 00 resulting solution was stirred under a nitrogen atmosphere for 16 hours. The solution was concentrated in vacua, and the residue was Clpartitioned between 15 mL H 2 0 and 15 mL Et 2 O. -The aqueous phase was extracted with 5 mL Et2O, then the aqueous phase was acidified with aqueous citric acid. The acidic aqueous phase was saturated with NaCI and extracted with 3 x 15 mL EtOAc. The EtOAc extracts were combined, dried (Na2SO4), then filtered and concentrated in vacua to give 40 mg of the title compound as a white foam. 1H NMVR

(CD

3 OD, 300 MHz, two rotameric forms) 8 2.85 3H), 2.94-3.25 (br m, 3H), 3.35-3.70 (br m) and 3.64 4 H total), 3.70-3.97 (br in), 3.74 3.76 3.78 3.79 3.81 and 4.03 (br d, J=14 Hz, 8H total), 4.43 (AB, 1H), 5.91 and 5.93 2H total), 6.50-6.60 (in, 1H), 6.67- 7.02 (br m, 6H), 7.29 (br d) and 7.35 (br d, 2H total). HRMS calcd for C31 H 35 N208 563.2393. Found: 563.2385.

Examole 74 trans. tran~s-2-(4-Methoxy~henlF- 4 3-benzodioxol-5-yi)-l1-(N- (34dim ethoxybenzyl)amingcarbonylm ethyl~Drrolidine3ca rboxylic acid The procedure of Example 73C was used, with the substitution of the resultant compound from Example 73A for the resultant compound from Example 7313, to provide the title compound. IH NMR (CD 3 OD, 300 MHz) 8 2.85 J=1l6Hz, I1H), 2.92 (br t, J=9Hz, 1 2.98 (br t, J=1lOHz, 1 3.32-3.39 (br m, 2H), 3.54-3.65 (br m, 1 3.67 3H), 3.78 (s, 3H), 3.80 3H), 3.85 J=10 Hz, 1H), 4.21 J=15Hz, 1H), 4 .41. J 1 5.91 2H), 6.67 J=8Hz, 1 6.75-6.95 (in, 7H), 7.33-7.40 (in, 2H). HRMS calcd for C 30 H32N208 549.2237. Found: 549.2224.

WO 99/06397 PCT/US98/15479 00 -128- F-ample (2R.3R .4R)-2-(4-MethoXyphenl)-4-( 1.3-benzodioxol-5-yI)- 1 1 dioropylaMinocarbonl)l- butyl)pyrrolidine-3-carboxylic -acid 00 Eagl ~trans. trans-2-(4-MethoXyghenyl)- 4 .3-beozodioxol-5-yl)- 1 Rjz (benzyloxcarbonflyFbutyl)gyrrglidi ne-3-carboxylic acid ethyl ester The procedure of Fung, et. al., J. Med. Chem., 35(10): 1722-34 00 (1992) was adapted. The resultant compound from Example GA (103 mg, 3- 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 Na 2 CO3 and 25 mL of CH 2 CI2. The aqueous phase was extracted with 2 x 10 mL CH2CI2, 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 o solid. 1H NMR indicated the presence of two diastereomeric products.

trans. trans-2-(4-Methox=h enyl?)-4-( 1.3-benzodioxol-5-yl)- 1 1 N-7 din1rooylaminor~arbonl)l- butyfl~vrrolidine-3-carbOxylic acid ethyl ester The resultant compound from Example 75A (101 mg, 0.180 mmol) and 30 mg of. 10% palladium on charcoal were stirred in 2 mL EtOAc under 1 atmosphere of H2 for 4 hours. The reaction mixture was filtered through a plug of Celite, using 15 mL MeOH to wash the catalyst., The combined filtrate and wash were concentrated in vacua 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 mmot), 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-di methyl amino0propyl) carbodii mide hydrochloride (44 mg, 0.23 mmol) was added. the mixture was stirred at -15 0 C and allowed to warm slowly to room temperature overnight. The solvent was removed by distillation under reduced pressure, and the residue WO 99/06397 PCT/US98/15479 00 -129was partitioned between 20 mL EtOAc and 10 mL of 1 M aqueous Na2003.

ciThe 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.

00 SFurther purification of overlap fractions by preparative TLC eluting with 1:2 Et 2 O-hexane yielded 32 mg of a less polar product, and ci44 mg of a more polar product.

00 Examgle (2R.3R.4R)-2-(4-Methoxylhenyl)- 4 .3-benzodtigxol-5-yl R)-1 (N.N-dipropylaminocarbonyl)-l -butyl)pyrrolidi e-3-carboxylic 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. [MD~ 520 (c=0.235,

CH

3 OH). 1 H NMR (CD 3 OD, 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 mn, 2H), 2.94-3.02 (br m, 2H), 3.20-3.40 (mn, overlapping with CD 2 HOD signal), 3.40-3.60 (br M. 2H), 3.79 3H), 4.04 (br d, J=9 Hz, 1H), 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 in, 3H), 7.29-7.39 (in, 2H). MS m/z 525 (M+H) 4 Example 76 2 S.35.4S1 -2-(4-Methoxyphenyl- 4 -(l.3benzodioxol-5yl)-1 R-1-I (N.N-diprooylaminocarbonyl)- -butyflpyrrglidine3carboxylic 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 73B3, to provide the title compound in 88% yield. [cz]D +580 (c=0.37,

CH

3 OH). 1 H NMR (CD 3 OD, 300 MHz) 8 0.57 (br t, J=7Hz, 3H), 0.88-0.98 (in, 6H), 1.08-1.35 (br in, 2H), 1.35-1.68 (br mn, 4H), 1.75-1.90 (br m, 1H), 2.75-2.86 (br in, 2H), 3.10-3.30 (br m, 2H), 3.51-3.65 (br in, 2 3.69 3H), .4.03-4.16 (br mn, 2H), 5.91 2H), 6.71-6.83 (mn, 2H), 6.86-6.97 (mn, 3H), 7.32 (br d, J=9Hz, 2H). MS m/z 525 WO 99/06397 PCTIUS98/15479 00 -130- Eaml~le 7 (2S.3S.4s)-2-(4-MethoMypheflyl)-4-(1- 3-benzodioxol-5-yl)-l1-((1

N-

dio~ronylaminocarboflyl)-1 -butyl~pyrrolidine,-3-carboxylic -acid 00 Example 7A trans. trans-2-(4-Methoxypheflyfl- 4 .3-benzodioxol-5-yl)-l S)-1 (N .N-dipropylaiminocarbonl)l- butyl)Dyrrolidine-3-carboxylic acid 00 0 (2R)-N,N-dipropyl 2-hydroxypentaflamide (106 mg, 0.528 mmol, cimade by standard procedure) was dissolved in 2 niL THIF under an argon atmosphere, diisopropylethylamifle (75 mg, 0.58 mmol) was added, then the solution was cooled to -20 00. Trifluoromethaflesulforlic anhydride 159 mg, 0.565 mmol) was added to the cooled solution over 1 minute, and the reaction mixture was stirred at -20 00C for 1 hour, and at room temperature for an additional 1 hour. The resulting slurry was recooled to 0 00, and a solution of the resultant compound from Example 6A (195 mg, 0.528 mmol) and diisopropylethylamifle (101 75 mg, 0.58 mmol) in 3 ml of CH 2 CI2 was added. The reaction was stirred at 0 00 for 3 hours and for an additional 2 days at room temperature.

TLC

(Et 2 O-hexane 1:2) indicated starting materials remained, so the mixture was warmed to reflux for 4 hours. The reaction was cooled, then partitioned between 30 mL EtOAc and 15 mL of 1 MAaqueous Na2C03. 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 vacua to a yellowish oil. Purification by flash 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.

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

Exam~Z 77 (2S.3S4S (4-MethoYhenyl)-4-( 1.3-benzodioxol-5-yfl-l dilrogylamiflocarbonl)l- butyl)pyrrglidifle-3-carboxyliC, acid The procedure of Example 730 was followed, with the substitution of the less polar isomer from Example 77A for the resultant product from Example 73B, to provide the title compound in 100% yield. 1 H NMR

(CD

3 OD, 300 MHz) and MS identical to those of Example 750.

WO 99/06397 PCT/US98/15479 00 S-131- Example 78 (2R.3R.4R -2-(4-Methoxvhenvl)-4-(1.3-benzodioxol-5-vl--1-((1S)-1L-(N.diDrovylaminocarbonvl-l-butvl)ovrrolidine-3-carboxylic acid The procedure of Example 73C was followed, with the substitution oo 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 0 (CD30D, 300 MHz) and MS identical to those of Example 76.

00 Example 79 trans. trans-2-(4-Methoxvyhenvl)- 4 .3-benzodioxol-5-ll- l-(N.N-diln- 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 mixture was cooled in an ice bath, and 25% solution of ammonia in methanol was added. After 30 minutes, the solid which had formed was filtered, washed with ethanol and finally with ether to yield 850 mg of the 3-carboxamide compound. m.p. 194-196

°C.

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

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

To this nitrile in 5 mL toluene was added 385 mg of trimethyl tin chloride and 126 mg sodium azide. The mixture was heated 20 hours at 125 °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 1H NMR (CDCI3, 300 MHz) 8 0.85 J=7Hz, 3H), 0.87 WO 99/06397 PCT/US98/15479 00 -132- S 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=gHz, 1H), 4.37 J=9Hz, 1H1), 5.86 2H), 6.62 (d, J=BHz, 1H), 6.65-6.73 (in, 3H), 6.95 J=2Hz, 1H), 7.11 J=9Hz, 2H).

00 Eage8 trans. trans-2-(4-Fluoroohelyfl-;4-( 1. 3-benzodioxol-5-yl)- 1- (NN-dffn- 0 butvl)aminocarbflylflethyvlpyrrolidine-3-carboxylic acid 00 The title compound was prepared as an amorphous solid from methyl (4-flourobenzoyl) acetate and 5-(2-nitrovinyl)-1 ,3-benzodioxole CI using the procedures described in Examples 1 and A43. 1 HNMR (CDCI3, 300 MHz) 8 0.81 J=7Hz, 3H), 0.90 J=7Hz, 1.0-1.55 (mn, 8H), 2.81 J=13 Hz, 1H), 2.90-3.10 (in, 4H), 3.15-3.30 (in, 1H), 3.32-3.45 (mn, 3H), 3.55-3.65 (in, 1H), 3.86 J=lIOHz, 5.94 (dd, J=2Hz, 4Hz, 2H), 6.72 J=8 Hz, 1 6.86 J= 8 Hz, 1 6.95-7.07 (in, 3H), 7.32- 7.45 (in, 2H-).

Exml~le 8 trans, trans-2-(4-Metho~yohenl)f-4-( 1.3-benzodioxol-5-yfl- 1 N-di(nbu tvflam in ocarbonl miethyfl)pYrrl idie3ca rboyl ic acid N,N-Dibutyl glycine (150 mng, 0.813 inmol), prepared by the method of Bowman, J. Chem. Soc. 1346 (1950), in 0.7 mL of THF was treated with 138 mng (0.852 inmol) carbonyldiimidazole and heated for minutes at 50 OC. After cooling to room temperature, 250 mng (0.678 inmol) of ethyl trans, trans-2-(4-inethoxyphenyl) 4 belzo di oxol- 5-yl) -pyrroli die3-ca rboxyl ate, the compound resulting from Example 6A, was added, and the mixture was heated at 45 00 for minutes. The product was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate to give 306 mng 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. H NMR (CDC13, 300 MHz) 6 rotational isomers 0.75 and 0.85 (2 t, J=7Hz, 3H), 1.05-1.5 (in, 2.65-3.20 (in, 6H) 3.43-3.70 (in, 3H), 3.72 3H), 3.87 J=l5Hz, 11H), 4.49 (dd, J=l2H-z, 6Hz) and 5.23 (dd, J=l2Hz, 8Hz) 2H, 5.90 (dd, J=2Hz, 4Hz, 6.63-6.78 (mn, 3H), 6.86 and 7.04 (d, J=9Hz, 2H), 7.22 J=9Hz, 2H).

WO 99/06397 PCr/US98/15479 00 0 -133- Fxapl 8 trans, trans-2-(4-Meth oXylhenyfl-4-( 1. 3-benZodioxol-5-yfl- 1 p ropylam inoca rbony m ethyl) pyrro Iid ine-3- ca rboyl ic acid The title compound was prepared using the procedures described 00 in Example 1. m.p. 160-162 0 C. 1 H NMVR (CDCI 3 300 MHz) rotational ~'isomers 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=l3H-z, 1H), 2.90-3.10 (mn, 4H), 3.23- NI 3.61 (in, 5H), 3.71 and 3.75 (two doublets, J=lOHz, 1H), 3.78 3H), 00 S5.92-5.96 (in, 2H), 6.72 J=8Hz, 1H), 6.83-6.89 (in, 3H), 7.03 J=2Hz, 1c 1H), 7.81 J=9H-z, 2H).

toans. trans-2-(4-Metho~yheflyl)-4-( 1. 3-benzodioxol-5-yl)- 1 N-di(np2ropyI)am inocarbony~ethyllDyrrolidine--carboxylic acid The compound resulting from Example 6A (250 mng, 0.677 minol), 205 mg (1.36 mmol) diallyl acrylamide (Polysciences, Inc.), and 10 mg acetic acid were heated at 85 OC in 0.75 mL of methoxyethanol for one hour. Toluene was added, and the solution was washed with bicarbonate solution, dried, and concentrated. Chromatography on silica gel eluting with 3:1 hexane-ethyl acetate gave 283 mng of the diallyl compound.

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

The ester was hydrolyzed to the title compound by the method of Example I D in 83% yield. I H NMR (CDCI3, 300 MHz) 8 0.82 and 0.83 (two triplets, J=7Hz, 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 (mn, I1H), 3.51-3.61 (in, 1IH), 3.73 (d, J=12H, 1H), 3.75.(s, 3H), 5.94 2H), 6,71 J=9Hz, 1H), 6.79-6.85 (mn, 3H), 7.04. J=2Hz, 1H)< 7.32 J=9Hz, 2H).

WO 99/06397 PCT/US98/15479 00 -134- Example 4 trans, trans-2-(4-Methoxyphgnyfl-4-( 1.3-benZodioxol-5-yl)- I N-di(n- N- butyl)aminocarbonyF~oyrrolidine-3-garboxylic acid The -title compound was prepared by the procedures described in 00 Example 8 using dibutyl carbamoyl chloride, prepared by the method of SHoshino et al., Syn. Comm., 17: 1887-1892 (1987), as a starting material. 1 H NMR (CDCI3, 300 MHz) 8 0.86 J=7Hz, 6H), 1.14-1.28 (in, c 4H), 1.35-1.48 (mn, 4H), 2.81-2.94 (in, 2H), 3.11 J=l2Hz, 1H), 3.30- 00 3.41 (in, 2H), 3.59-3.68 (mn, 2H), 3.76 3H), 3.78-3.85 (mn, 1H), 5.81 (di 0 J=9Hz, 1H), 5.94 2H), 6.73-6.86 (in, 5H), 7.24 J=9Hz, 2H).

Example 8 trans. trans-2-(4-Methoxypenyfl-4-( 1.3-benzodioxol-5-yl)- 1 -AN N-dimn butvli)aminocarbonlmethl)Dyrrolidile-3-carboxylic acid sodium salt Sodium hydroxide (48.2 mng of 98.3% pure, 1.184 inmol) in 2 mL of MeOH was added to the compound resulting from Example 43 (610 mg, 1.196 mmol.) in 5 mL MeOH. The solution was concentrated to dryness, and the resulting powder was stirred with heptane. The heptane was removed in vacuo to give a powder which was dried in the vacuum oven for 2 hours at 60 OC to yield 627.5 mg of the title compound.

Exaga 8 trans. trans-2-(4-Methoxyhenyl)-4- (1 .3-benzodioxol-5-yl)- 1 -r2-(N.N-di(nbutyflam ino'ethyl]Dyrrolidine-3-carboxylic acid A solution of the broinoethyl compound resulting from Example 61A (150 mg), dibutylamine (150 mg) and sodium iodide (18 mg) in 0.75 mL ethanol was heated at 80 0 C for 1 hour. After cooling, toluene was added, and the solution was washed with potassium bicarbona te solution, dried over Na2SO4 and concentrated. More toluene was added, and the solution was again concentrated to get ridpof excess dibutylainine. The residue was dissolved in warrn) heptane and filtered from a small amount of insoluble material. The hepane was removed in vacua to give 143 mng of the intermediate ethyl ester.

The ester was hydrolyzed by the method of Example 1 D to give the title compound as a white powder. 1 H NMR (CD 3 OD, 300 MHz) 8 0.89 (t, J=7Hz, 6H), 1.16-1.30 (in, 4H), 1.44-1.56 (in, 4H), 2.48-2.57 (in, 1H), 2.80-3.08 (mn, 8H), 3.14-3.25 (in, 1H), 3.31-3.38 (in, 1H), 3.59-3.60 (in, WO 99/06397 PCT/US98/15479 00 -135- 1IH), 3.74 3H), 3.75 J=lOHz, 1H), 5.89 2H), 6.71 J=9Hz. 1H), 6.81 (dd, J=9Hz, 2Hz, 6.90 J=lOHz, 2H), 6.96 J=2Hz, 1H), 7.37 S(d, J--l-OHz, 2H-).

00 xmle8 trans. trans-2-(4-Methoxyghenyl)-4-( I .3-benzodioxol-5-yi)l- .N-di(nbutyl~am inoca rbonyl)-N-methylaminoethlDvrrolidile-3-carboxylic acid N- Dibutyl carbamoyl chloride (135 mg) was added to the compound 00 C) resulting from Example 61B (250 mg) and 150 mg triethylamine in 1 mL Sdichloromethane. After stirring 1 hour at room lemperature, 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 1 D to afford 141 mg of the title compound. 1 H NMR (CD 3 OD, 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 3.00-3.20 (mn, 8H), 3.44-3.55 (in, 1H), 3.62-3.78 (in, 2H), 3.80 3H), 4.07 J=12 Hz, 1H), 5.93 2H). 6.75 J=9Hz, 1H), 6.87 (dd, J=9Hz, 2Hz, 1H), 6.94 J=10 Hz, 2H), 7.04 J=2Hz, 1H), 7.40 (dI J=lOHz, 2H).

trans, trans-2-(4-Methoxyghenyfl-4-( 1.3-benzodioxol-5-yl)- 1 N-di(nbutyflam inocarbonylnethyl1yrrol idin-3 (N-m eth anesulfolYIca rboxa mide Carbonyl- diimidazole (75 mng, 0.463 mmol) was added to 150 mg (0.294 inmol) of the compound resulting from Example 43 in 0.4 mL of tetrahydrofuran, and the solution was stirred at 60 00C for. 2 hours.

After cooling, 50 mng (0.526 minol) of inethanesulfonamide and 68 mng (0.447 minol) of DBU in 0.3 mL of THE 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. 170-173 0 C. 1 H NMR (CDCI3, 300 MHz) 8 0.82 (t, J=7Hz, 0.88 J=7Hz, 3H), 1.05-1.51. (in, 8H), 2.75-2.86 (in, 2H-), 2.83-3.25 (in, 4H), 3.17 3H), 3.32-.3.50 (in, 3H), 3.70-3.78 (in, 1H), 3.80 3H), 3.87 J=lOHz, 1H), 5.96 (dd, J=2Hz, 4Hz, 2H), 6.74 (d, WO 99/06397 PCTIUS98/15479 -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).

Exame8 0C) trans. trans-2-(4-Methoxyo~henyl)-4-( 1.3-benzodioxol-5-yl)- 1 N-di(nbutflaminocarbonlmethyl)6rrolidine-3-(N-benzenesulofll)carboxamide The compound resulting from Example 43 was converted to the N~ title compound by the method of Example 88 substituting 00 Sbenzenesulfonamide for methanesulfonamide. m.p. 169-171 OC for a Ssample recrystallized from acetonitrile. 1H NMR tCDC13, 300 MHz) 8 0.81(t, J=7 Hz, 3H), 0.89 J=7Hz, 3H), 1.02-1.50 (in, 8H), 2.65-2.80 (in, 2H), 2.90-3.25 (in, 4H), 3.80-3.95 (in, 3H), 3.50-3.60 (in, 1H), 3.65 (d, J=lOHz, 3.81 3H), 5.94 2H), 6.70 2H), 6.81-6.90 (in, 3H), 7.17 J=lOHz, 2H), 7.55 J=7 Hz, 2H), 7.66 J=7Hz, 1H), 8.95 (d, J=7Hz, 2H).

trans, trans-2- (4-Methoxyghenyl)-4-( 1.3-benzodioxol-5-fl)-1 -rN. N-di(n-butyl) amiosulfonylmethvll-12yrrolidine--carboxyic acid Chloromethyl sulfenyl chloride, prepared by the method of Brintzinger et. al., Chem. Ber. U: 455-457 (1952), is reacted with dibutylamine by the method of E. Vilsmaier described in Liebigs Ann.

Chem. 1055-1063 (1980) to give N,N-dibutyl chloromethyl sulfenyl chloride. Alternatively dimethyl(methylthio)sulfonium tetraf lou robo rate is reacted with dibutylamine to give N,N-dibutyl methylsulfenyl chloride which is chlorinated with N-chlorosuccinimide to give chioromethyl sulfenyl chloride by the method of E. Vilsmaier, described in the above reference.

The N,N-dibutyl chioromethyl 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.

WO 99/06397 PCT/US98/1 5479 00 00 -137- Example 91 trans.trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl 1-(N.N-di(nbutvl)aminocarbonvl-1 -RS)-ethvllDvrrolidine-3-carboxvlic acid 00oo Example 91 A (+--Dibutyl 2-bromooropanamide 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 CI2, the solution was cooled to 0 °C under a N 2 atmosphere, and then treated dropwise with isobutyl chloroformate 0 (0.45 mL 3.5 mmol). After 10 minutes at 0 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 Na 2

CO

3 solution, then the organic phase was washed sequentially with mL of 1 M aqueous NaHSO4 and 25 mL brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 698 mg (2.64 mmol, 79 of the crude bromoamide as a colorless oil. 1 H NMR (CDCl 3 300 MHz) 8 0.93 J=7Hz) and 0.97 J=7.5Hz, 6H total), 1.26-1.60 7H), 1.60-1.78 1H), 1.82 J=6Hz, 3H), 3.04-3.27 2H), 3.42-3.64 2H), 4.54 J=7H, 1H). MS (DCI/NH 3 m/e 264 and 266 Example 91 B trans.trans- and cis. trans-2-(4-MethoxyDhenyl-4- 1.3-benzodioxol-5-vl)- di(n-butyl)aminolcarbonyl-l-(RS)-ethyl)ovrrolidine-3-carboxvlic acid ethyl ester A solution of the resultant mixture of trans,trans and cis,trans compounds from Example 1C (232 mg, 0.628 mmol) and the resultant compound from Example 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 Et20 and 10 mL of 1 M aqueous Na 2 C03 solution. The organic phase was washed with 20 mL water and 20 mL brine, dried over Na 2

SO

4 filtered and concentrated under reduced pressure to afford the crude amino amide as a brown oil (339 mg, 98% crude). The product was obtained by flash chromatography on silica gel eluting with EtOAc-hexane to provide 224 mg of the title compounds as a mixture of 4 diastereomers. 'H NMR (CDCl 3 300 MHz) 5 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 WO 99/06397 PCT/US98/15479 0O9/697PTU98157 -138- S (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 (in, 5H), 7.38-7.43 (in, 2H). MS (DCI/NH3) mle 553 00trans, trans-2-(4-Methoxyhenyl)-4-( 1.3-benzodioxol-5-yfl-1

N-

dibutylamino)carbonyl-1 .(RS)-ethyl)pyrrolidine-3-carboxylic acid The procedure of Example 73C was used, substituting the resultant N- compound from Example 91 B for the resultant compound from Example 73B to give 00 the title compound in 61% yield. 1 H NMR (CD 3 QD, 300 MHz) 8 0.70-1.05 (several m, 1. 14 J=6Hz, 211), 1. 17-1.55 (in, 611), 2.79-3.03Jin, 3.5H), 3.20-3.65 (br m, 4.6H plus CD 2 HOD), 3.70-3.78 (in, 0.4H), 3.79 3H), 3.98 J=8Hz, 0.611), 4.06 J=7.5Hz, 0.4H), 4.25 J=8Hz, 5.92 and 5.94 2H total 6H), 6.73 (d, and 6.75 J=3Hz, 1 H total), 6.78-6.85 (in, 1 6.91-7.00 (in, 3H), 7.30- 7.38 (mn, 2H). MS (DCIINH 3 Wne 525 Anal calcd for C 30

H

4

ON

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

Exampel2 trans, trans-2-(Pentyl)-4-( 1 3-benzodioxoI-5-yl)- 1-(N .N-di(nbutyflaminocarbonylmethyl)1yrrolidine-3-carboxylig acid Exa~lle 92A Methyl 2-(4-hexenoyl)-4-n itro-3-( 1 .3-benzodioxole-5-yl~ butyrate A solution of methyl 3-oxo-6-octenoate (502 mg, 2.95 minol) in 10 mL of isopropanol was added to a solution of 5-(2-nitrovinyl)-1 ,3-benzodioxole (712 mng, 3.69 minol) in 10 mL THF, then DBU (22 ILL, 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 ke toester. The solution was concentrated in vacuo and flash chromatographed on silica gel eluting with 18% ethyl acetate in hexane to produce 879 mng (2.42 inmol, 82%) of the title compound as a mixture of diastereomers in a 1:1 ratio. 1 H NMR (CDCI3, 300 MHz) 8 1.55-1.66 (mn, 3H), 2.02-2.17 (br m, 1 2.20-2.37 (in, 1.5H), 2.49-2.76 (in, 3.57 1.5H), 3.74 1.5H), 3.97 J=7.5H, 0.5H) and 4.05 J =BHz, 4.10-4.20 (in, 1IH), 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 7.5H-z, 1 MS (DCI/NH3) m/e 381 (M+NH 4 4 Anal calcd for C 18

H

21 N07: C, 59.50; H, 5.82; N, 3.85. Found: C, 59.32; H, 5.71; N, 3.72.

WO 99/06397 PCT/US98/15479 00 O -139- Example 92B Methyl trans.trans-2-(Dentyl)-4-(1.3-benzodioxol-5-vllDVrrolidine-3-carboxvlate The procedures of Example 18 and Example 1C were followed, with the substitution of the resultant compound from Example 92A for the resultant oo 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 N conditions. A solution of the crude compound (660 mg, 2.07 mmol) in 3 mL 00 C methanol was treated with a solution of sodium methoxide (made by the addition of i 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 CI2. The aqueous phase was extracted (2 x 30 mL CH 2 CI2), then the combined organic phases were washed with 20 mL brine, dried over Na 2 SO4, filtered and the filtrate concentrated under reduced pressure to afford the crude product. Purification by flash chromatography on silica gel eluting with 3.5% methanol in CH 2

CI

2 gave 336 mg the title compound as a yellow oil. 1H 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, 2H), 3.53 J=9Hz, 1H), 3.66 3H), 5.94 2H), 6.65-6.75 3H). MS (DCI/NHa) m/e 320 Anal calcd for C18H 25 N0 4 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-vl)-1 -(N.N-di(nbutylaminocarbonvlmethyllDvrrolidine-3-carboxylic 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 (CDCI3, 300 MHz) 8 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.

WO 99/06397 PCT/US98/15479 0O9/690CTU9/57 00 -140- Example 9 trans, trans-2-(Pentyfl-4- (1 .3-benzodioxol-5-vl)- 1 -r2-(N-gropyl-N- CI propylsulfonylamino~ethyllpyrrolidine-3-carboxylc acid 00 Eamnl~l 9A __Methyl trans. trans-2-(pentyl)-4- (1 .3-benzodioxol-5-yfl)- 1-(2-brom oethyl)pyrrolidins- The procedure of Example 61 A was used, with the substitution of the 00 C) resultant compound from Example 92B for the resultant compound from Example 0 1iC, to provide the title compound as a yellow oil. I 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, 2H), 2.76- 2.91 (mn, 2H), 3.10-3.22 (in, 2H), 3.36-3.47 (mn, 2H), 3.68 3H), 5.92 2H), 6.69- 6.77 (in, 2H), 6.90-6.94 (mn, I1H). MS (DCI/NH 3 m/e 426, 428 Methyl trans, trans-2-(Pentyl)-4-( 1.3-benzodioxol-5-yl)- 1 -r2-(N-Qropyl-Nprogylsulfonylamino~ethyl1yrrolidin-3-carboxylate A solution of the resultant compound from Example 93A (102 mng, 0.24 iniol) and tetrabutylainmonium iodide (6 mg, 16 pinol) in 1 mL EtCH was treated with propylamine (60 4±L, 0.73 iniol). The solution was warmed to 80 0 IC 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 2 003. 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

CI

2 diiosopropylethylamine (65 iL-, 0.373 iniol) was added, followed by propylsulfonyl chloride (29 iL-, 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 vacuo. Purification by flash chromatography eluting with 20% ethyl acetate in hexane provided 65.0 mg of the title compound as a waxy solid. Rf 0.17 (20%EtOAc-hexane). MS (DCI/NH 3 in/e 511 WO 99/06397 PCT/US98/15479 00 -141trans. trans-2-(Pentyh)-4-( 1. 3-benzodioxol-5-yl)- 1 -[2-(N-propyl-Nc-i Dropylsulfonylamino)ethyllpyrrolidine-3-carboxylic acid The procedure of Example 710 was followed, with the substitution of the 00 resultant compound from Example 93B for the resultant compound from Example S71 B, to provide the title compound as a white foam (47 mg, Rf 0. 14 S(5%MeOH-CH2CI2). I H NMR (CDC1 3 300 MHz) 8 0.88 (br t) and 0.92 J=7Hz, 6H Stotal), 1.22-1.52 (br m, 6H), 1.63 (sextet, J=8Hz, 2H), 1.75-2.10 (br m, 4H), 2.89-2.98 00 (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), S6.71 J=8Hz, 1H), 6.77 (dd, J=1.5,8Hz, 1H), 6.89 J=1.5Hz, 1H). MS (DCIINH3) We 497 Examl 4 trans. trans-2-(Prolyl)-4-(1 .3-benzodioxol-5-yfl- 1 N-di(nbutyl) aminocarbonylmethyl~yrrolidine-3-carboxylic acid Ethyl 2-(4-butanoyl)-4-n tro-3- (1 The procedure of Example 92A was followed, with the substitution of ethyl butyryl acetate for methyl 3-oxo-6-octenoate, to provide the title compound as a mixture of trans and cis isomers (47 mng, Rf 0.28 (25%EtOAc-hexane).

'H

NMR (CDCI3, 300 MHz) 850.74 J=7.5Hz) and 0.91 J=7.5Hz, 3H total), 1.08 (t.

J=7Hz) and 1.28 J=7Hz, 3H total), 1.45 (sextet, J=7Hz, 1 1.63 (sextet, J=7Hz, approx. 1.5H), 2.17 J=7Hz) and 2.24 J=7Hz, 0.5H total)2.40-2.5 4 (in, 1IH), 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). MVS (DCI/NH3) W/e 369 Anal calcd for 0 17

H

21 N07: C, 58.11; H, 6.02; N, 3.99. Found: C, 58.21; H, 5.98; N, 3.81.

Examle94 Ethyl trans. trans-2- (groyi) 4 1.3 ben zod ioxo 1-5- ylyrrolid ine-3- carboxylate 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 WO 99/06397 PCT/US98/15479 0O9/697PTU98I57 00 -142- Example94C trans, trans-2-(Progyfl4-( 1.3-benzodioxol-5-y)- 1 N-di(n- CI butflaminocarbonylm ethyl)-pyrrolidine-3-carboxylic cid The procedure of Example 92C was followed, with the substitution of the 00 resultant product from Example 94B for the resultant product from Example 9213, to C give the title compound. 1 H NMR (CDCI3, 300 MHz) 860.89 J=7.5Hz), 0.92 (t, and 0.97 J=7.5H, 9H total), 1.22-1.80 (br m, 12H), 2.83 J=7.5Hz, 1 H), S3.40-3.55 (br m, 2H), 3.55-3.68 1H), 3.78 J=l 5Hz, 1 5.92 J=1 Hz, 2H), 00 6.70 J=8Hz, 1 6.79 (dd, J=l1Hz,8Hz, 1 6.90 J=1lHz, MS (DCIINH 3 W ne 447 Anal calcd for C 25

H

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

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

(2R.3R.4S)-(+)-2-(4-Methoxyohenyl)-4-(1 .3-benzodioxol-5-yl)-1 1-(tertbutyloxycarbonyl-am inocarbonylmethyl)-pyrrolidine-3-carboxylic acid Exam~J 9A trans. trans-2-(4-MethoXyphenyfl-4-( 1. 3-benzodioxol-5-yl)- 1 -(rtertbutyloxycarbonylam inocarbonyim ethyllpyrrolidine-3-carboxylic acid The resulting mixture of 64% trans,trans- and cis,transpyrrolidines resulting from Example 1C (3.01 g, 8.15 mmol) was dissolved in 50 mL of methylene chloride. To this was added dropwise a solution of di-tert-butyl dicarbonate (1.96 g, 8.97 minol) in 20 mL methylene chloride under a nitrogen atmosphere, and the resulting solution was stirred 30 minutes at which point TLC (ethyl acetate:hexane, 1:1) indicated that all of the starting material was consumed. The reaction mixture was concentrated and dried under high vacuum to give 3.94 g of the ethyl ester as a yellow-brown oil. 1 H NMR

(CDCL

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

The reaction mixture was vigorously stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated to remove ethanol, diluted with 250 mL of water and extracted three times with WO 99/06397 PCT/US98/1 5479 00 O -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 (Na 2 SO4), filtered, concentrated and dried oo on high vacuum to give the title compound as a white foam (2.19 g, 1 H NMR (CDCI3, 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), N 6.71-6.79 3H), 6.84-6.91 2H), 7.19 J=9 Hz, 2H). MS (DCI/NH 3 00 O m/e 442 Example (2R.3R.4S)-(+)-2-(4-MethoxvDhenyl)-4-(1.3-benzodioxol-5-vl- 1-(tertbutyloxvcarbonvlaminocarbonvlmethvl)-ovrrolidine-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 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 (Na 2 SO4), filtered, concentrated and dried on high vacuum to a white powder (550 mg, 55 of theoretical 50 maximum; >99.5 ee). 1 H NMR (CDCI 3 300 MHz) 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 WO 99/06397 PCT/US98/15479 00 0 -144- Example (2R.3R.4S)-(+)-Ethyl 2-(4-methoxyphenyl)-4-(1.3-benzodioxol-5-yl)-Dvrrolidine-3carboxvylate The compound resulting from Example 95B (251 mg, 0.568 mmol) oo 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 CN dissolved. The reaction mixture was concentrated to a solid which was oo 0 partitioned between 0.8 M aqueous sodium carbonate (50 mL) and methylene chloride (50 mL). The aqueous layer ywas further extracted with methylene chloride (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated and dried under high vacuum to give the title compound as an almost colorless oil (158 mg, 1H NMR (CDCI 3 300MHz) 5 1.11 J=7 Hz, 3H), 2.18 (v br s, 1H), 2.93 J= 9 Hz, 1H), 3.19,3.22 (dd, J=7 Hz, 1H), 3.50-3.69 2H), 3.80 3H), 4.07 J=7 Hz, 2H), 4.49 J=9 Hz, 1H), 5.94 2H), 6.73 J=2 Hz, 2H), 6.81-6.92 3H), 7.34-7.41 2H). MS (DCI/NH 3 m/e 370

(M+H)

Example 42R.3R.4S)-(+-2-(4-Methoxvyhenll-4-(1 .3-benzodioxol-5-vl-1 -(tertbutyloxvcarbonvl-aminocarbonvlmethyl)-Dyrrolidine-3-carboxvlic acid To the resulting compound from Example 95C (131 mg, 0.355 mmol) was added, diisopropylethylamine (137 mg, 185 gL, 1.06 mmol), acetonitrile (2 mL), N,N-di-(n-butyl)bromoacetamide (133 mg, 0.531 mmol), and the mixture was heated at 50 for 1.5 hours. The reaction mixture was concentrated to a solid, dried under high vacuum, and purified by chromatography on silica gel eluting with 1:3 ethyl acetatehexane to give pure ester as a colorless oil. 1 H NMR (CDCI3, 300MHz) 8 0.81 J=7 Hz, 3H), 0.88 J=7 Hz, 3H), 1.10 J=7 Hz, 3H), 1.00-1.52 8H), 2.78 J=14 Hz, 1H), 2.89-3.10 4H), 3.23-3.61 5H), 3.71 J=9 Hz, 1H), 3.80 3H), 4.04 J=7 Hz, 2H), 5.94 (dd, J=1.5 Hz, 2H), 6.74 J=9 Hz, 1H), 6.83-6.90 3H), 7.03 J=2 Hz, 1H), 7.30 J=9 Hz, 2H). MS (DCI/NH 3 m/e 539 (M+H) To the ethyl ester dissolved in 7 mL of ethanol was added a solution of lithium hydroxide (45 mg, 1.06 mmol) in water (2.5 mL). The mixture was stirred for 1 hour at ambient temperature and then warmed WO 99/06397 PCT/US98/15479 00 O -145slowly to 40 over 2.5 hours at which point all of the starting material had been consumed. The reaction mixture was concentrated to Sremove the ethanol, diluted with 60 mL water and extracted with ether (3 x 40 mL). The aqueous solution was treated with 1 N aqueous oo 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

C

NI dried (Na 2 SO4), filtered, concentrated and dried under high vacuum to O give the title compound as a white foam (150 mg, 1H NMR (CDCI3, N 300MHz) 6 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/NH3) m/e 511 (M+H) [a] 22 +74.420. Anal calcd for C29H 3 BN2O6 .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 Alternate Preparation of (2R.3R.4SS-(+)-2-(4-Methoxyphenyl)-4-(1.3-benzdioxol-5yl)-1-(tert-butyloxycarbonvlaminocarbonylmethvl)-prrolidine-3-carboxylic acid The product of Example 95A (2.858 g) was suspended in 10 mL of EtOAc. 0.7833 g of R alpha methyl benzylamine in 3 mL ethyl acetate was added. On swirling all of the solids were dissolved. The ethyl acetate was removed in vacuum. Ether (13 ml) was added to the residue. When all of the residue had dissolved, 5 mg of seed crystals were added and these crystals were crushed with a metal spatula while cooling in ice. The product crystallized very slowly. After 1 hour the solid was filtered and washed with ether giving 1.4213 g, m.p. 163- 167°. 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. 102-110°. (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 WO 99/06397 PCTIUS98/15479 00 -146- Sstirring for a few minutes the crystals were filtered. Yield: 1.401 g, m.p. 164.1720.

Treatment of the crystalline product with 10% citric acid and ether according the method described in Example 95B provided the title 00 compound.

00 trans. trans-2-(4-Methoxvphenyl)-4-( 1.3-benzodioxol-5-fl)- 1 -[2-(N-oroI2Xl-NbLutvrylam ino~ethyl1Dyrrolidine-3-ca rboxylic 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 ±CI18) 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 (CDC13, 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 m, 2H), 3.48 (br mn, 4H), 3.76 (br m, 2H), 3.78 3H), 4.30 (br s, 1 5.95 2H), 6.75 (d, 1H, J=8Hz), 6.84 (in, 1IH), 6.85 2H, J=8Hz), 7.04 1IH, J=lHz), 7.40 2H, J=8Hz). MS (DCI/NH3) m/e 497 Anal calcd for

C

2 eH3 6

N

2 O6 1.0 TFA: 0, 58.82; H, 6.42; N, 4.57. Found: 0, 58.77; H, 6.30; N, 4.42.

Exmple 9 trans. trans-2-(4-Methoxyaheflyl-4-( 1.3-benzodioxol-5-yl)- 1 -r2-(N-Drol2yl-N- (ethylam inocarbonyl) am ino~ethvllpyrrolidine-3-carb oXlic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for inethylainine in Example 61B and ethyl isocyanate for isobutyryl chloride in Example 61C. The crude product was purified by trituration with 1:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC13, 300 MHz) mixture of rotamers 8 0.80 J=8Hz) and 1.05 J=8Hz) and 1.20 (in) and 1.42 (in) total of 8H for the four peaks, 2.35 (br s, 1H), 2.70 (in, 1IH), 3.0 (in, 3H), 3.2 (in, 3H), 3.25 (dq, 1H, J=1,8Hz), 3.42 (mn, 1H), 3.6 (in, 1H), 3.75 (in, 1 3.78 3H), 4.8 (br s, 1 5.95 2H), 6.74 1 H, J=8H1z), 6.85 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS (001/NH 3 m/e 498 WO 99/06397 PCT/US98/15479 00 -147- SAnal calcd for C 27

H

3 sN 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.

Exampe 9 00 trans. trans-2-(4-Methgxyheflyl)-4- (1 .3-benzodigxol-5-yF). 1 -r2-(N-butyl-Nbutyrylamino~ethylllyrrolidifle-3-carboxylic acid The title compound was prepared by the methods described in 00 Example 61, but substituting butylamine for methylamine in Example 61GB and butyryl chloride for isobutyryl chloride in Example 61C. The Scrude product was purified by trituration with 1 :1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.80 (in, 3H), 0.90 3H, J=8Hz), 1.45 (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, 3.80 (br m, 2H), 3.82 (s, 4.30 (br s, 1 5.95 2H), 6.75 I1H, J=8Hz), 6.84 (in, 1 6.85 2H, J=8Hz), 7.04 11H, J=lHz), 7.40 2H-, J=8Hz). MS (DCI/NH3) mWe 511 HRMS calcd for C 29

H

3 8N206: 511.2808. Found: 511.2809 trans. trans-2 (4-Methoxvphenyfl-4-( 1.3-benzodioxol-5-yl)- 1 -r2-(N-D2ropyl-Nethoxycarbonylamilo~ethyllpyrrolidine-3carboXylic 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. 1H NMR (COCl 3 300 MHz) 8 0.80 3H, J=8Hz), 1.05 (mn, 2H), 1.22 (in, 3H), 1.45 (mn, 3H), 2.08 (br s, 1IH), 2.75 (in, 1 2.88 (br q, 2H, J=BHz), 3.08 (br 2H), 3.27 (br m, 2H), 3.44 (in, 3.54 (dt, 1H, J=1,8Hz), 3.63 1H, J=BHz), 3.78 (s, 4.02 (br d, 2H), 5.93 2H), 6.72 1 H, J=8Hz), 6.81 (dd, I1H, J=1,8Hz), 6.85 2H-, J=8Hz), 7.00 1H), 7.30 2H, J=8Hz). MS

(DCI/NH

3 in/e 499 Anal calcd for C 27

H

34 N207 -0.5 H20: C, 63.89; H, 6.95; N, 5.52. Found: C, 64.03; H, 6.71; N, 5.30.

WO 99/06397 PCT/US99/15479 00 -'148- Example trans. trans-2-(4-Methoxyhfenyl4( 1.3bnzodiogol-5-yi)l -r2-(N-m ethyl-N- (2ethyl butvrvl)amin tyeyroiie3-abxlc acid To -the compound resulting from, Example 61 B (190 mg) dissolved 00 in THIF (2 mL) was added HOBt (60 mg), EDGI (85 mg), Nmethylmorpholine (50 pL), and DMF (2 mL). 2-Ethylbutyric acid was Iadded and the solution stirred overnight at ambient temperature. Water Ni (10 mL) was added, and the mixture was extracted with EtOAc (2 x 00 SmL). The combined organic extracts were washed with saturated Ssodium bicarbonate solution, 1 IN1H 3 P 04, and brine, dried with Na2S 04, 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. 1H NMR (CDCI3, 300 MHz) (mixture of rotamers) 8 0.66, 0.74, 0.80, 0.88 (all triplets, total of 6H, J=BHz), 1.05 (in, 2H), 1.25-1.75 (in, 5H), 2.16 (mn, 1H), 2.32 (in, 1H), 2.45 (mn, 1 2.70 (mn, 1 2.86, 2.94 total 3H), 2.95 (mn, 1 3.35 (in, I1H), 3.52 (mn, 2H), 3.65 (in, 1 3.80 3H), 5.94, 5.96 total 2H), 6.73 (in, 1H), 6.84 (in, 3H1), 6.97 (in, 1H), 7.30 (in, 2H). MS (DCI/NH 3 in/e 497 Anal calcd for C 28

H

36

N

2 0 6 -0.25 H 2 0: C, 67.11; H, 7.34; N, 5.59. Found: C, 67.13; H, 7.24; N, 5.56.

ExmilA1 trans. trans-2-(4-Methoxvheflyl)-4-( 1 3-benzodioxol-5-vfl- 1 -r2-(N-methyl-N-(2- 1Drolylvaleryflamyino~ethyll1Dyrrolidine-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 4±C18) 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 (CDCI3, 300 MHz) 8 0.79 3H, J=8Hz), 0.82 3H, J=8Hz), 1.10 (mn, 4H), 1.2-1.5 (in, 4H), 2.55 (mn, 1 2.96 3H), 3.15 (br m, 1 3.32 (br m, 1 3.56 (in, 2H), 3.68 (in, 1 H) 3.68 3H), 3.70 (mn, 1 3.80 (in, 2H), 4.65 (br d, 1 5.92 2H), 6.75 1 H, J=8H1z), 6.84 (mn, 1 6.85 2H, J=8Hz), 7.05 1H), 7.42 2H, J=8Hz). MS (DCI/NH3) m/e 525 WO 99/06397 PCT/US98/15479 00 -149- Anal calcd for C 30

H

4

ON

2 06 -1.25 TFA: C, 58.51; H, 6.23; N, 4.20.

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

EamgIl1Q 00 trans. trans-2-(4-Methoxyphenyl)-4-(1 .3.benzodioxol-5-y)- 1 -r2-(N-propyl-N-(tert- __buylxjcarbonylm ethyl)am in oethyllDyrrolid in -3-carboXylic acid The title compound was prepared by the methods described in (1Example 61, but substituting propylamine for methylamine in Example 00 0 61B and t-butyl bromoacetate for isobutyryl chloride in Example 610.

c~The crude product was purified by trituration wIMh 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 (CDCI3, 300 MHz) 8 0.82 3H, J=8Hz), 1.18 (in, 2H), 1.19 9H), 2.12 (in, 1H), 2.46 (in, 2H), 2.70 (in, 3H), 2.85 (mn, 2H), 3.20 2H), 3.40 (dd, 1H, J=2,8Hz), 3.50 (dt, 1IH, 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=BHz). MS (DCI/NH 3 m/e 541 Anal calcd for

C

30 H4ON207 -1.0 H 2 0: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.75; H, 7.35; N, 4.86.

trans. trans-2-(4-MethoXylhenyl)-4-( 1.3-benzodioxol-5-yfl- 1 -r2-(N-PrQPYl-N-(flpropylaminocprbony1m ethyl) am ino~ethyllpyrrolidin e3carox~lic acid The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylamine in Example 61 B and N-propyl bromoacetamide for isobutyryl chloride in Example 610. The crude product was purified by preparative HPLC (Vydac 1 iC1 8) 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

(CDCI

3 300 MHz) 8 0.78 3H, J=BHz), 0.88 3H, J=8Hz), 1.45 (in, 2H), 1.48 (in, 3H, J=8Hz), 2.55-2.7 (mn, 2H), 2.90 (in, 1H), 3.04 (in, 1H), 3.15 (in, 3H), 3.28 1 H, J=8Hz), 3.45 1 H, J=8Hz), 3.60 (mn, 2H), 3.70. (d, 2H, J=8Hz), 3.75 (in, 1 3.80 3H), 4.25 1 H, J=8Hz), 5.95 2H), 6.75(d, 1H, J=8Hz), 6.86 (dt, 1H, J=1,8Hz), 6.88 2H, J=BHz), 7.04 (d, 1H, J=lHz), 7.40 2H, J=BHz). MS (DCI/NH3) m/e 526 (M+H) 4 Anal calcd for C 29 H39N306 -1.85 TEA: C, 53.32; H, 5.59; N, 5.70. Found: C, 53.45; H, 5.62; N, 5.63.

WO 99/06397 PCTIUS98/15479 00 -150- Examp*l trans.trans-2-(4- MethoXyo~henvl)-4- (1 3-benzodioxol-5-fl)-l 41 -r2rool~m-N-(4methoXygh enoxycarbonvl~am ino)ethvllgyrrolidine-3-carboxylic acid 00 The title compound was prepared by the methods described in ~'Example 61, but substituting propylamine for methylamine in Example 561 B and 4-methoxyphenylChloroformate for isobutyryl chloride in 0 C) 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 (m,3H1), 1.57 (in, 2H1), 2.45 (br s) and 2.60 (br s, total of I1H), 2.90-3.15 (mn, 4H), 3.42-3.7 (in, 3.78 3H), 3.80 3.85 (in) and 4.0 (in, total of 1 5.95 and 5.98 total of 6.63(m, 6.72 1H-, J=8Hz), 6.81 (in, 2H), 6.93 (in, 5H), 7.40 (in, 2H). MVS (DCI/NH3) mWe 577 Anal calcd for

C

32

H

36 N208 1.0 H 2 0: C, 64.63; H, 6.44; N, 4.71. Found: C, 64.70; H, 6.38; N, 4.63.

Eampiii 105 trans. trpns-2-(4- Methoxyphenyl)-4- (1 3-benzodioxol-5-yfl- 1 -I2-(N-Prolyl-N-(4m ethoxybenzoyfl aming)ethllgyrrlidile-3-carboxyliC ci The title compound was prepared by the methods described in Example 61, but substituting propylamine for methylainine in Example 61 B and anisoyl chloride for isobutyryl chloride in Example 61 C. The crude product was purified by trituration with 1:1 diethyl ether-hexane.

The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) mixture of rotainers 8 0.78 (in) and 0.98 J=8H-z) total of 3H, 1.47 (in) and 1.52 (q, J=8Hz) total of 2H, 2.25 (br s, 11H), 2.78 (br s, 2.90 (br t, 2H), 3.12- 3.68 (mn, 3.80 3.82 3H), 5.94 2H), 6.75(d, 11-, J=8Hz), 6.83 (mn, 5H), 6.94 (in, 1 7.22 (in, MS (FAB) m/e 561 Anal calcd for C 32

H

3 6N207 -0.75 H 2 0: C, 66.94; H, 6.58; N, 4.88. Found: C, 67.00; H, 6.38; N, 4.59.

WO 99/06397 PCTIUS98/1 5479 00 -151trans. trans-2-(4-Methonymheflyl)-4-(1 .3-benzodioxol-5-yI)- 1 -r2-(N-Dropyl-N- __ben zoylam ino~ethyl pyrrolidin e-3-carboxylic acid The title compound was prepared by the methods described in 00 Example 61, but substituting propylamnine for methylamine in Example 61B and benzoyl chloride for isobutyryl chloride in Example 61C. The crude product was purified by tritu ration with 1:1 diethyl ether-hexane.

Ni The resulting solid was dissolved in CH 3 CN and water and lyophilized to 00 0 give the product as a white solid. 1H NMR (CDCI3, 300 MHz) mixture of Srotamers 8 0.65 and 0.9 (in, total of 3H) 1.4 and 1.55 (in, total of 2H), 2.05 and 2.15 (mn, total of 1 2.6 3.6 (in, 8H), 5.92 2H), 6.70(d, I1H, J=BHz), 6.82 (in, 4H), 7.2 7.4 (in, 6H). MS (DCI/NH3) W/e 531 Anal calcd for C 3 jH 34 N206 0.3 H 2 0: C, 69.46; H, 6.51; N, 5.23. Found: C, 69.48; H, 6.19; N, 4.84.

trans, trans-2-(4-Metho~vhenYl- 4 -(1.3-benzodoxpl-5-vfl- 1 -12-(N-progyl-Nbenzyloxvcarboflylaino~) ethyl pyrrol idi ne-ca rboxlic acid The title compound was prepared by the methods described in Example 61, but substituting propylainine for inethylaine in Example 61B and benzyl chloroformate for isobutyryl chloride in Example 61C.

The crude product was purified by preparative HPLC (Vydac pC 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 0.8 (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 (mn, 2H), 3.66 (in, IH), 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 (mn, 3H). MS (FAB) Wne 561 Anal calcd for C 32 H36N207 -1.0 TFA: C, 60.53; H, 5.53; N, 4.15.

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

trans. trans-2-(4-MethoxylhenyI)- 4 (1 .3-benzodioxol-5-yfl- 1 -l2-(N-Drolyl-N-(4methoxvbnzyloxycarbonyl~am ino~ethyll1Dyrrolidine-3-carboxylic acid The title compound is prepared by the methods described in Example 61, substituting propylamine for methylamine in Example 61 B WO 99/06397 PCT/US98/15479 00 -152and 4-methoxybelzyl chloroformate for isobutyryl chloride in Example CI610C.

Examgle109 00trans. trans-2-(4-MethOxy~helyl)-4-( 1. 3-benzodioxol-5-Vfl)-1 -r2-(N-bubfi-Nethoxyca rbonylamino~ethyllt'yrrolidile-3-carboXylic acid The title compound was prepared by the methods described in 00 Example 61, but substituting butylamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 610.

The crude product was purified by preparative HPLC (Vydac .C 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 3H), 4.06 (q, 2H, J=8Hz), 4.35 (br s, 1 5.94 2H), 6.76 1 H, J=BHz), 6.92 2H, J=BHz), 7.03 (br s, I 7.17 (br s, 1 7.7 (br s, 2H). MVS (FAB) m/e 513 Anal calcd for C 28

H

36 N207 -0.5 TFA: C, 61.15; H, 6.46;, N, 4.92.

Found: C, 60.99; H, 6,80; N, 4.93.

Examlle 110Q trans. trpns-2-( 4-Methoxynhenfl)l 4 (1 .3-benzodioxol-5-yfl 1 -r2-(N-butyl-N- 12o~xcroyamn~tyl roidn--abxLaids, The title compound was prepared by the methods described in Example 61, but substituting butylainine for methylamine. in Example 61B and propyl chloroforrfate 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 0.80 (br s, 1H), 0.85 3H, J=8Hz), 0.92 (br s, 1H), 1.22 (in, 3H), 1.40 (in, 3H), 1.62 (br m, 1 2.15 (br s, I 2.72 (in, 1 2.87 (mn, I1H), 3.1-3.45 (nm, 5H), 3.55 (mn, 1 3.64 1 H, J=8Hz), 3.79 3H), 3.88 (br s, 1H), 3.97 (br s, 1H), 5.95 2H), 6.73(d, 1H, J=8Hz), 6.85 (mn, 3H, 1H), 7.30 2H, J=8Hz). MS (FAB) m/e 527 Anal calcd for 0 29

H

38 N207 -0.15 H 2 0: C, 65.80; H, 7.29; N, 5.29. Found: C, 65.79; H, 7.30; N, 5.2 1.

WO 99/06397 PCTIUS98/15479 00 -153trang. trans-2-(4- Methoxyphenyl)-4-( 1 -3-benzodioxol-5-yfl-l 1 2-(N-propyl-Nprpoxycpgrbonylamino~ethyllpyrrolidne3carboxylic acid The title compound was prepared by the methods described in 00 Example 61, but substituting propylamine for methylamine in Example ~'61B and propyl chioroformate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl etherci hexane. The resulting solid was dissolved in CH3CN and water and 0 l yophilized to give the product as a white solid. 1H NMR (CDCI3, 300 MHz) 8 0.80 3H, J=BHz), 093 (in, 3H), 1.43 3H), 1.62 (in, 1 2.15 (br 1 2.68-3.45 (mn, 8H), 3.54 (in, 1 3.66 (in, I 3.78 3H), 3.94 (in, 2H), 5.94 2H), 6.72 I1H, J=8Hz), 6.82 (in, I1H), 6.84 2H, J=8Hz), 7.00 (br s, 1H), 7.33 (in, 2H). MS (DCI/NH3) m/e 513 Anal calcd for C 28 H36N207 -0.15 H 2 0: C, 65.26; H, 7.10; N, 5.44. Found: 0, 65.22; H. 6.74; N, 5.06.

Exali112 trans, trans.- 1 N-Di (n-butyl)m inocarbonylmethyfl-2 .4-di (1.3-benzodoXol-5fOgyrrolidine-3-carboXylic acid Ethyl (3,4-methylenedioxybenzoyl)acetate, prepared by the method of Krapcho et al., Org. Syn. AZ, 20 (1967) starting with 3,4inethylened ioxyacetopheflone instead of 4-m ethoxyaceto pheflone, was reacted by the procedures described in Example 1 to give the title compound as a white solid. m.p. 58-60 0 C. 'H NMR (CDC13, 300 MHz) 8 0.87 (quintet, J=6Hz, 6H), 1.12 (sextet, J=6Hz, 2H), 1.24-1.51 (in, 61H), 2.80 J=l3Hz, 1H), 2.94-3.12 (in, 4H), 3.28-3.50 (in, 4H), 3.58-3.62 (in, 1H), 3.78 J=9Hz, 1H), 5.95 4H), 6.73 (dd, J=8Hz, 3Hz, 2H), 6.84-6.89 (in, 2H), 6.92 J=lHz, 7.01 H=lHz, 1H). MS (DCI/NH3) We 525 trans. trans-I1 (n-Butyl)N-progylsultoflYlam ino)ethyl)-2-(4-metho)(ypheflYl) 4

A

(1 3 ben ioXl-5YlDyrrolidile3acaoYLIcacid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 64-65 1 H NMR (CDC13, 300 MHz) 8 0.83 J=7Hz, 3H),+0.98 J=7Hz, 3H), 1.12-1.25 (mn, 2H), 1.32-1.41 (in, 2H), 1.75 (sextet, J=7Hz, 2H), 2.23-2.31 (in, 2H), 2.72-3.32 (in, 8H1), WO 99/06397 PCT/US98/15479 00 -154- 3.43 (dd, J=9Hz, 3Hz, 1 3.53-3.59 (in, 1 3.65 J=9Hz, 1 3.80 (s, S3H), 5.95 2H), 6.73 J=8Hz, .1 6.83 (dd, J=8Hz, 1 IHz, 1 6.88 (d, J=9Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=9Hz, 2H). MS (DCI/NH3) W/e 547 00 Example 114 -trans. trans-i N-Di(n-butyU)am inocarbonlmethyl)2-(4-inethoXV=henvi)- 4 .3- 00 ben zodioxol- 5-yfl)yrr I id ife-3-carboxylic acid Using the procedures described in Examples 28 and 43, the title compound was prepared as a white solid. m.p. 74-J76 0 C. 1 H NMR (CDC13, 300 MHz) 8 0.80 J=6Hz, 3H), 0.88 J=8Hz, 3H), 1.08 (sextet, J=8Hz, 2H), 1.21-1.48 (in, 6H), 2.75 J=l2Hz, 2.95-3.09 (in, 4H), 3.26-3.59 (in, 5H), 3.75 J=gHz, 1H), 3.79 3H), 4.28 4H), 6.78 (d, J=9Hz, 1H), 6.85 J=9Hz, 2H), 6.91 J=3Hz, 9Hz, 1H), 6.98 (d, J=3Hz, 1 7.32 J=9Hz, 2H). MS (DCI/NH3) m/e 525 Examgle 115 trans. trans- 1-(2-(N-Progvl-N-DropyI sulf onylam ino'~ethyP)-2-(4-inethoxylhenfl)- 4 (1 .3-benz!odioxol-5-yfl pyrrolidine-3-caroxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-73 00. IH NMR (CDCI3, 300 MHz) 8 0.79 J=8Hz, 3H), 0.98 J=8Hz, 1.43 (sextet, J=8Hz, 2H), 1.75 (sextet, J=8Hz, 2H), 2.22-2.32 (in, 1H), 2.69-3.32 (in, 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=llHz, 11H), 6.83 (dd, J=lHz, 11Hz, 1H), 6.87 (d, J=1l1Hz, 2H), 7.0 J=2Hz, 1 7.32 J=1l1Hz, MIS (DCI/NH3) mle 533 Examole 116 trans. trans-i 1 -2N-BilNbtlufnlmioehl2-4mhxyhnl)41.3- Dyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 62-63 00. 1 H NMR (CDC13, 300 MHz) 8 0.82 J=6Hz, 0.91 J=6Hz, 1.20 (sextet, J=6Hz, 2H), 1.33- 1.42 (in, 4H), 1.68 (quintet, J=6Hz, 3H),2.23-2.32 (mn, 1H), 2.70-3.28 (in, 9H), 3.41 J=8Hz. 3.52-3.58 (in, 3.65 J=8Hz, 1H), 3.79 (s, WO 99/06397 PCT/US98/15479 0O9/697PTU98I57 -155- S3H), 5.95 2H), 6.72 J=8Hz, 1 6.82 J=BHz, 1 6.87 J=8Hz, 2H), 7.01 1H), 7.32 J=8Hz, 2H). MS (DCI/NH 3 m/e 561 00 trans, trans-i N-Di (n-butyl)am inocarbonylmethyl)-2-(4methoxymethoxyphenyfl)-4-(1.3-benzodioxo-5-ylDyrrolidile-3-carboxylic acid 4-Hydroxyacetophenone was treated with chioromethyl methyl CIether and triethylamine in THF at room temperature to give ethyl 4- 00 0 met ho xym eth oxybe nzoyl acetate which was treated by the procedures cidescribed in Example 1 to afford the title compotmd as a white solid.

m.p. 48-49 OC. 1 HNMR (CDC13, 300 MHz) 8 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, 4H), 3.25-3.35 (in, 1H), 3.40 J=l2Hz, 1H), 3.43-3.52 (in, 2H), 3.47 3H), 3.55-3.62 (mn, 1H), 3.77 J=9Hz, 1H), 5.15 2H), 5.94 (in, 2H), 6.73 J=8Hz, 1H), 6.86 (dd, J=lHz, 8Hz, 1H), 7.0 J=8Hz, 2H), 7.04 J=lHz, 1H), 7.32 (d, J=BHz, 2H). MS (DCt/NH 3 m/~e 541 trans. trans- 1 N-Di (nbutyl~aminocarboflYlmethyl)-2- (4-hydroxylhenyl)- 4 (l 3- .benzodioxol-5-l)yrrolidile-3-carboxylic acid hydrochloride salt The compound resulting from Example 11.6 was treated with concentrated HCt in 1:1 THE-isopropanol to give the title compound as a white solid. m.p. 211-2120 OC IH NMR (CD 3 OD. 300 MHz) 8 0.90 (t, J=8Hz, 611), 1.12-1.27 (in, 6H), 1.36-1.45 (in, 2H), 3.04 (bs, 1H), 3.14- 3.35 J=9Hz, 1H), 3.90 (bs, 3H), 4.17 J=l5Hz, 1H), 5.96 2H), 6.82-6.93 (in, 4H), 7.03 J=lHz, 1H), 7.42 (bs, 2H). MS (DOI/NH 3 mWe 497 30Exml11 trans. trans-i1 (N-l sobutyl- N-12rogyls u If onylam ino)ethyl)-2-(4-m eth oxyphenl)-4- (1 .3-benzodioxol-5-y)1Dyrrolidifle-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. in.p. 73-74 OC. 1 H NMR (0D01 3 300 MHz) 8 0.80 J=6Hz, 6H), 0.98 J=8Hz, 3H), 1.62 (sextet, J=6Hz, 1H), 1.74 (sextet, J=8Hz, 2H), 2.23-2-34 (mn, 1H), 2.68-2.98 (in, 7H), 3.08-3.18 (in, WO 99/06397 PCT/US98/15479 00 -156- 1IH), 3.26-3.42 (in, 2H), 3.52-3.58 (in, 1 3.65 J=9Hz, 1 3.80 (s, 3H), 5.90 2H), 6.74 J=8Hz, 1 6.82 J=8Hz, 1 6.86 J=8Hz, 2H), 6.98 J=1lHz, 1 7.33 J=8Hz, 2H). MS (DCI/NH3) m/e 547 (M44H))+ 00 Eamgle 120 0 trans, trans-i -(-NBneeufnlNgoyaioehl--4mtomey)4 COO (1 .3-benzodioxol5-vyl12rrolidifl9-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 89-91 0 C. 1 H-NMR (CDCI 3 300 MHz) 8 0.74 J=6Hz, 3H), 1.33 (sextet, J=6Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.72 (in, 1H), 2.85-3.05 (mn, 4H), 3.12-3.22 (in, 1H), 3.38 (dd, J=3Hz, 9Hz, 1H), 3.49-3.57 (in, 1H), 3.62 J=9Hz, 1H), 3.82 3H), 5.96 2H), 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, 7.70 J=7Hz, 2H). MS (DCI/NH3) m/e 567 trans. trans- 1 (-N(-ehxbnee~fny)Nnoyaioehl--4 methoxyghenyfl-4- (1 .3-benzodioxol-5-yl~Dyrrolidig-3-carboXylic- acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 96-97 0 1 H NMR (CDCI3, 300 MHz) 8 0.73 J=7Hz, 3H), 1.34 (sextet, J=7Hz, 2H), 2.20-2.30 (in, 1H), 2.62- 2.71. (in, 1H), 2.82-3.03 (in, 4H), 3.08-3.18 (mn, 2H), 3.38 (dd, J=3Hz, 9Hz, 1 3.48-3.56 (in, 1 3.62 J=9Hz, 1 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, 2H). MS (DCI/NH3) m/e 597 F~xmQj2I12 trans. trans-i N-Di(n-butyflaminogarbonomnethyfl-2-(2-methOXyethoXy4C methoxyphenyl)-4-(l1.3-benzod ioxol-5-yl)oyrroidine-3-carboxyic acid 2-Hyd roxy- 5-methoxyacetOP he none was treated with sodium hydride and bromoethyl methyl ether in THF at 70 0 C to provide ethyl 2m ethoxyethoxy-4-inethoxybenzoyl acetate which was treated by the procedures described in Example 1.to provide the title compound as a white solid. in.p. 63-65 00. 1 H NMR (CDCI3. 300 MHz) 8 0.84 J=7Hz, WO 99/06397 PCT/US98/15479 00 -157- 3H), 0.89 J=7Hz, 3H), 1.16 (sextet, J=7Hz, 2H), 1.28 (sextet, J=7Hz, 2H1), 1.45-1.52 (in, 4H), 2.87-2.94 (in, 2H), 3.00-3.16 (in, 3H1), 3.26-3.36 (in, 2H1), 3.43 3H), 3.47-3.54 (in, 3H), 3.66-3.72 (in, 2H1), 3.78 3H), 3.76-3.84 (in, 111), 4.02-4.10 (in, 4.25 J=9Hz, 1H), 5.92 2H), 00 6.40 J=2H-z, 1H), 6.52 (dd, J=2Hz, 9H-z, 111), 6.70 J=8Hz, 1H), 6.83 (dd, J=lHz, 8Hz, 11H), 5.98 J=2Hz, 1H), 7.53 J=9Hz, MS 0 (DCI/NH 3 mle 585 (M+H)4.

00 Example 123 trans. trans-i 1 2(-rplN(.-jnehlezneurnlanioehl--4 methoxyphenyl)-4-( 1.3-benzodioxol5-ylDyrrolidifle-3-carboxylc acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-90 0 C. 'H NMR (CDCI3, 300 MHz) 8 0.69 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.12-2.20 (mn, 1 2.32 3H), 2.47 311), 2.62-2.69 (in, 1 2.78 J=9Hz, 1 2.89 (dd, J=8Hz, 1 3.02 (sextet, J=9Hz, 2H), 3.15-3.32 (in, 3H), 3.46-3.55 (in, 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, 2H1), 6.97 J=lHz, 7.03 (bs, 2H), 7.29 J=9Hz, 1H). MS (DCI/NH3) m/e 595 Examp~le 124 trans, trans-- (2-(N-Propyl-N-(a-ch iororgroo~ylsulfonflain ino~ethyj)-2-(4methoxyohenyl)-4-(l .3-benzodioxol-5-yflDyrrolidifle-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 75-76 -DC. 1H NMR (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H1), 2.15-2.31 (mn, 3H), 2.70- 2.80 (in, 1H), 2.85-3.10 (mn, 6H), 3.23-3.31 (mn, 2H1), 3.43 (bd, J=9Hz, 1H), 3.55-3.66 (in, 4H), 3.81 3H), 5.94 2H). 6.73 J=8Hz, 1H1), 6.82 (d, J=8Hz, 1H), 6.86 J=8Hz, 2H1), 7.00 7.33 J=8Hz, 2H). MS

(DCI/NH

3 in/e 567 trans, trans- 1 (-NPoy--(-ehzehysl nlaioehI--4 inethoxyphenfl-4-( 3-benzod ioxol-5-vfl~gyrrolid ine,-3-carboxylicad Using the procedures described in Example 66, trans, trans- 1 (N-Propyl-N(vinysulfonyl)ainio)ethyl)2(4methoxyphenyl) 4 WO 99/06397 PCTIUS98/15479 00 -158benzodioxol-5-yl)pyrrolidiflG3-carboxylic acid was prepared. Ester S hydrolysis using aqueous sodium hydroxide in methanol afforded the title compound as a white solid. m.p. 62-64 00. 1 HNMR (CDCI3. 300 MHz) 8 0.78 J=7Hz, 3H), 1.42 (sextet, J=7Hz, 2H), 2.23-2.32 (in, 1H), 00 2.72-2.79 (in, IH), 2.86-3.05 (in, 4H), 3.10-3.27 (mn, 4H), 3.32 3H), 3.43 (dd, J=3Hz, 9Hz, IH), 3.53-3.58 (mn, 1H), 3.65 J=9Hz, 1H), 3.69 (t, (i J=6Hz, 2H), 3.80 3H), 5.94 6.73 J=BHz, 1H), 6.82 (dd, 00 J=lHz, 8Hz, 1H), 6.87 J=8Hz, 2H), 7.02 J=lHz, 1H), 7.33 J=8Hz, 0 2H). MS (DCI/NH 3 mle 549 trans. trans-i -(-NPoy-N(-toytylufn(ain~ty)2-4methoxyheflyfl- 4 -(l1.3-benzodioxol-5-yl~Dyrrolidie3carboxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 58-60 OC. 1 H NMR (00013, 300 MHz) 8 0.78 J=7Hz, 3H), 1.18 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2H), 2.24- 2.33 (in, 1H), 2.70-2.80 (mn, 1H), 2.87-3.05 (in, 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, I 3.72 J=6Hz, 2H), 3.80 3H), 5.95 2H), 6.73 J=7Hz, 1H), 6.83 (dd, J=lHz, 7Hz, 1H), 6.87 J=8Hz, 2H), 7.00 J=lHz, 7.32 J=8H-z, 2H). MS (DCI/NH 3 m/e 563 Exangle 27 trans, trans- 1 (2-(N-PronylN(5-diinethylamino- nphthylsulf ony~lamliflowhyfl- 2 (4-methoXylhenl)- 4 1. 3-benzodioxol-5-yl)yrrolidie3-carboxylic aci Using the procedures described in Example 66, the title compound was prepared as a yellow solid. in.p. 102-104 00. I H NMR (00013, 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 2.72-2.89 (in, 1H), 3.05-3.12 (mn, 2H), 3.26-3.45 (in, 3H), 3.45-3.52 (in, 3.58 J=9Hz, 6.97 J=l1Hz, 1H), 7.13 J=7Hz, 1H), 7.26 J=8Hz, 7.42-7.50 (in, 2H), 8.08 (dd, J=lHz, 7Hz, 1H), 8.20 (d,-J=8Hz, 8.48 J=8Hz, 1H). MS (DCI/NH 3 Wne 660 WO 99/06397 PCT/US98/15479 -159trans, trans-i (2.(N.Propyl.N(ethylsulfonyl)aminlO)ethyl2(4-methoxyphenYl- 4 (1 .3.benzodoxol.5ylpyrroldile-3-carboxylic acid Using the procedures described in Example 66, the title compound 00 was prepared as a white solid. m.p. 70-72 OC. 1 H NMR (CDCI 3 300 MHz) 0.79 J=BHz, 3H), 1.28 J=7Hz, 3H), 1.43 J=8Hz, 2H), 2.22-2.30 1H), 2.71-2.80 (in, 1H), 2.82-3.10 (in, 6H), 3.18-3.32 (in, 2H), 3.43 c'l (dd, J=3Hz, 9Hz, 1H), 3.53-3.60 (in, 1H), 3.65 J=9Hz, 1H), 3.80 3H), 00 0 5.96 2H), 6.73 J=7Hz, 1H), 6.82 (dd, J=lHz, 7Hz, 1H), 6.88 (d, *ciJ=8Hz, 2H), 7.00 J=lHz, 7.32 J=8Hz, 2Hl). MS (DCI/NH3) Wle 519 Exmgle 29 trans. trans- 1 -(2..(N..Proyl..N-(4..methylbenzeflesulf onl~l'ajnifo)ethI- 2 4 methoxyghenl)-4- (1 .3.benzodioxol5VlD1vrrolidifle-3-carboXylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 78-79 1 H NMR (CDCI 3 300 MHz) 8 0.73 J=7Hz, 3H), 1.33 (sextet, J=7Hz, 2H), 2.20-2.30 (in, IH), 2.40 2.61-2.72 (in, 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, 3.62 J=9Hz, 1H), 3.81 3H), 5.95 2H), 6.73 J=8Hz, 1H), 6.82 J=8Hz, 1H), 6.87 J=8Hz, 2H), 7.00 1H), 7.21 J=8Hz, 2H), 7.29 J=8Hz, 2H), 7.57 J=8Hz, 2H).

MVS (DCI/NH 3 mle 581 Eall 3 trans. trans.. N.Di(n.butlaminocarbonlmlethyl)2-(3-pyridyl)- 4 (l.3ben zodioxol5VI)gyrrol id ie-3-arboXylic acid Methyl nicotinoyl acetate was prepared by the method of Wenkert, et al., J. Org. Chemn. 48: 5006 (1983) and treated by the procedures described in Example 1 to provide the title compound as a white solid.

in-p. 167-168 0 C. 1 H NMR (CDC13, 300 MHz) 8 0.82 J-7Hz, 3H), 0.89 J=7Hz, 3H), 1.14 (sextet, J=7Hz, 1.23-1.48 6H), 2.86-3.20 (mn, 6H), 3.34-3.43 (in, 2H), 3.57 (dd, J=3Hz, 9Hz, 1H), 3.75-3.83 (mn, 1H), 4.08 J=9Hz, IN), 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/NH3) Wne 482 WO 99/06397 PCT/US98/15479 00 -160- Examgle 1 trans. trans-i -(-NPoy--nbtlufnlaioehl--4mto~eyl4 00 (1 .3-benzodioxl-5-y'~Dyrrolidile-3-carboXylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 65-66 OC 1 H NMR (CDCI3, 300 MHz) 8N 0.78 J=7Hz, 3H), 0.92 J=7Hz, 3H), 1.3-1-1.46 (in, 4H), 1.68 00 (quintet, J=7Hz, 2H), 2.21-2.32 (in, 1H), 2.70-3.08 (mn, 7H), 3.12-3.23 (mn, 0 2H), 3.42 (dd, J=2Hz, 9Hz, 1H), 3.52-3.58 (mn, 1H), 3.64 J=9Hz, 1H), 3.80 3H), 5.96 2H), 6.72 J=7Hz, 1H), 6.83-(dd, J=lHz, 7Hz, 1H), 6.86 J=BHz, 2H), 7.00 J=lHz, 1H), 7.32 J=BHz, 2H). MS (DCI/NH3) Wle 547 trans. trans-i- (2-(N-Propyl-N-(4-chlorobelzgeflsulfgfllam ino~ethyfl-2-(4methoxyoheflyfl-4-( 1 .3benzodioxol-5-yfl~yrrolidie3-c rbocylic aid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 105-106 0 C. 'H NMR (CDCI3, 300 MHz) 8 0.72 J=-7Hz, 3H), 1.34 (sextet, J=7Hzm 2H), 2.56-2.62 (in, 1H), 2.78-2.86 (in, 1H), 2.96-3.03 (in, 3.13-3.26 (in, 3H), 3.51 (dd, 9Hz, 1H), 3.62-3.68 (in, 1H), 3.80 3H), 3.94 J=9Hz, 1H), 5.92 (s, 2H), 6.75 J=8Hz, 1H), 6.84 (dd, J=2Hz, 8Hz, 1H), 6.94 J=8Hz, 2H), 6.98 J=2Hz, 1H), 7.36 J=8Hz, 11H), 7.49 J=8Hz, 1H), 7.68 (d, J=8Hz, 1H). MS (DCI/NH3) m/e 601 Examole 133 trans.trans-1-2(-rgiN(ez Isloy~mn~ty)2-4mtoy~ev)4 (1 .3-benzodioxol-5-yl) Dvrrolidine-3-carboxvlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 88-89 0 C. 1 NMR (CDCl3. 300 MHz) 8 0.72 J=7Hz, 3H), 1.32 (sextet, J=7Hz, 2H), 2.06-2.16 (mn, 1H), 2.56- 2.67 (mn, 1H), 2.75-3.10 (mn, 6H), 3.30 (dd, J=2Hz, 9Hz, 1H), 5.95 2H), 6.73 J=7Hz, 1H), 6.80 (dd, J=lHz, 7Hz, 1H), 6.86 J=BHz, 2H), 6.97 J=lHz, 1H), 7.27-7.35 (mn, 7H). MS (DCI/NH 3 Wne 581 WO 99/06397 PCTIUS98/15479 00 -161c-i trans. trans-i .(2-(N-Prolyl-N(4flurbflelS ff~m ino)ethyl)-2- (4methoxyphenyfl-4-( 1 3-benzodioxol-5-y)12Yrrolidile-3-carboXyic acid Using the procedures described in Example 66, the title compound 00 was prepared as a white solid. m.p. 91-93 0 C. I H NMR (CDCI3, 300 MHz) 8 0.73 J=7Hz, 3H), 1.44 (sextet, J=7Hz, 2H), 2.18-2.27 (in, 1H), 2.56- (i2.67 (in, 1H), 2.78-2.87 (mn, 2H), 2.97 (septet, J=BHz, 2H), 3.11-3.1 6 (in, 00 2H), 3.33 (dd, J=2Hz, 9Hz, 1H), 3.43-3.50 (in, 1H), 3.57 J=9Hz, 1H), S3.78 3H), 7.08 J=8Hz, 2H), 7.24 J=8Hz, 2H), 7.69 (dd, 8Hz, 2H). MS (DCI/NH3) Wne 585 Examgle 135 trans. trans-i 1 (-ehlNpoyaioabnlehl--4mtoyhnl--4 benzouranyllyfDrrolidifle-acarboxylic acid Examgl3 Benzofuran-4-carboxaldehyde To a suspension of 60% sodium hydride in mineral oil (4.00 g, 100 inmol, 1.25 eq) in DMF (60 mL) at 0 OC'was added a solution of 3bromophenol (13.8 g, 80 inmol) in DMF (5 mL). After 10 minutes, bromoacetaldehyde diethyl acetal (14.9 inL, 96.6 minol, 1.24 eq) Was added, and the resultant mixture then heated at 120 00 for 2.5 hours.

The mixture was cooled to room temperature and was poured into water, and extracted once with ether. The organic solution was dried over MgSO4, filtered, evaporated and vacuum distilled to yield a colorless liquid (17.1 g, b.p. 160-163 0 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 iniol) 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 0 DC at 0.6 mm Hg.

To a solution of the above compounds (8.11 g, 41.5 iniol) in ether (80 inL) at -78 OC was added 1.7 M t-butyllithium (48.8 mL, 83 minol, 2 eq) such that the temperature did not exceed -70 00. After stirring for minte, e snhition of DMF (6.5 mL, 83 minol, 2 eq) in ether (20 mL) WO 99/06397 PCT/US98/15479 00 0 -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 00 with 10% ether in hexanes to yield benzofuran-6-carboxaldehYde (1.22 Sg) and benzofuran-4-carboxaldehyde (1.86 both as colorless oils.

Examgle 135 00 trans, trans-I 1 (N-Methyl-N-propyl-am inocarbonylm ethyl)-2(4-methoxYhenl)- 4 4 benzofuranyl~yrrolidine-3-carbo)CYtI 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. IH NMR (300 MHz, CDC13) (minor rotamer) 8 7.59 (1H, t, J=3Hz), 7.4-7.2 (6H, in), 6.8 (2H, d, J=8Hz), 4.03 (1IH, in), 3.94 (1 H, dd, J=8Hz, 3Hz), 3.77 (3H, 3.61 (1 H, dd, J=8Hz, 7 3Hz), 3.42 (1H, dd, J=lIHz, 5Hz), 3.40-2.90 (5H, in), 2.82 (2.81) (3H, s), 1.50 (2H, septet, J=7Hz), 0.82 (0.75) (3H, t, J=7Hz). MS (DCI/NH3) m/e 451 Anal.calc. for C 26

H

30 N205 -AcOH: C, 65.87; H, 6.71; N ,5.49.

Found: C, 66.04; H, 6.42; N, 5.60. s Example 136 trans, trans-i1 (N-Methyl-N-1rolmilocarboflylmethl2(4methoxyghenul) 4 -(6 benzouraly)Dyrrolid ine-3-carboxylic acid The title compound was prepared using the procedures described in Examples 1 and 49 substituting benzofuran-6-carboxaldehyde, prepared as described in Example 135A, in Example 49A for piperonal.

1H NMR (300 MHz, CDC13) (minor rotamer) 8 7.65 (1H, bd), 7.60 (1H, d, J=2Hz), 7.55 (1H, d, J=BHz), 7.35 (3H, in), 6.85 (2H, dd, J=8Hz, 3Hz), 6.75 (1H, dd, J=3Hz, 2Hz), 3.83 (2H, in), 3.79 (3H, 3.60-3.0 (7H, in), 2.91 (2.83) 3H), 1.51 (2H, septet, J=7Hz), 0.83 (0.78) (3H, t, J=7Hz). MS (DC I/NH 3 m/e 451 Anal.calc. for C 26

H

30 N205 0.5 H 2 0: C, 67.96; H, 6.80; N, 6.10. Found: C, 67.90; H, 6.71; N, 6.07.

WO 99/06397 PCTIUS98/15479 00 -163ci trans, trans. 1 N-Mty-N-2o1y mi caroymehl 2 4Mehwey)--6 ben zo-2.3-dihyd rof uranyl) yrrol idine-3-ca rboxy i g acid The title compound was prepared by catalytic hydrogenation (4 00 atopeeofHinA Hfloebypeaaiehi)oth C topee fH n cH olwdb reaaiehl)o h Scompound resulting from Example 136 1 H NMR (300 MHz, CDCI3) (minor 0 rotamer) 8 7.49 (7.47) (2H, d, J=8Hz), 7.19 (1H, d, J=8Hz), 7.00 (1H, in), op 7.82 (3H, in), 5.40 (1H, dd, J=llHz, 7Hz), 4.58 (2H, t, J=8Hz), 4.18 (1H, m 4.10 (1 H, mn), 3.88 (1 H, in), 3.79 (3H, 3.60 (1 H, mn), 3.35 (1 H, in), c-~3.19 (2H, t, J=8Hz), 3.00 (4H, mn), 2.91 (2.78) 1.53 (1.40) (2H, septet, J=7Hz), 0.88 (0.78) (3H, t, J=7Hz). MS (DCI/NH3) Wne 453 Anal.calc. for C 26

H

3 2N205 -1.25 TFA: C, 57.53; H, 5.63; N, 4.71. Found: C, 57.68; H, 5.68; N, 4.70.

Examl~le 138 trans. trans-i1 N-~~-uy~mncroymtyl--4mtixlhnl--4 benzofuranyl)12yrrolidile-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-4-carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl bromoacetarmde for N-m ethyl- N-propyl broinoacetamide. 1 H 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 01H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 4.02 (1 H, ddd, J=8, 6Hz,4Hz), 3.89 (1H, d, J=9Hz) 3.79 (3H, 3.67 (1H. dd, J=lOHz, 3Hz), 3.44 (2H, in), 3.35-3.15 (3H, mn), 3.00 (2H, mn), 2.84 (1H, d, J=l4Hz), 1.43 (3H, mn), 1.23 (3H, mn), 1.08 (2H, in), 0.87 (3H, t, J=7Hz), 0.82 t, J=7Hz). MS (DCI/NH3) ine 507 Anal.calc. for C 3 oH38N205:

C,

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

Example 139 trans. trans-i1 N.Di(n-butyl~amilocarboflylm ethyl)-2- (4-methOXY12hefyl)4-4 ben-zofuralyl)1Drrolidile-3-carbo)(ylic ~cid The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzofuran-5-carboxaldehyde, prepared by the procedures described in Exa 'mple 1 35A substituted 4broinophenol for 3-broinophenol, in Example 49A for piperonal and %9L 1-rPrcmae,tar ip fnr N -mnethyl- N -rropvl WO 99/06397 PCT/US98/15479 00 -164- Sbromoacetamide. 1 H NMR (300 MHz, CDCI 3 8 7.64 (1H, bd), 7.59 (1 H, d, N- J=2Hz), 7.43 in), 7.33 (2H, d, J=8Hz), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (IH, d, J=llHz), 3.89 (1H, d, J=9Hz) 3.79 (3H, s), 003.53 (1H, dd, J=lOHz, 3Hz), 3.44 (2H, mn), 3.30 (1H. mn), 3.20-2.95 (5H, in), S2.82 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H1, in), 1.08 (2H, mn), 0.87 (3H, St, J=7Hz), 0.82 t, J=7Hz). MS (DCIINH3) mWe 507 Anal.calc.

c for C 30

H

38

N

2 0,5: C, 71.12; H, 7.56; N, 5.53. Found: C, 70.73; H, 7.45; N, 00 5.29.

Eaml1lJ 140 trans. trans-I1 N- Di (n-butyl~)am! nocarbonyim ethyfl-2- methoxyghenl)f-4- (6benzofuranyl)yrrlidile-3-arboxylic acid The title compound was prepared by the procedures described in Examples I and 49 substituting benzofuran-6-Carboxaldehyde in Example 49A for piperonal and substituting N,N-dibutyl broinoacetainide for N-methyl-N-propyl broinoacetamide. 1 H NMR (300 MHz, CDCI3) 8 7.63 (1H, bd), 7.59 (1H, d, J=2Hz), 7.53 (IH, d, J=8Hz), 7.36 (3H, in), 6.85 (2H, d, J=8Hz), 6.73 (1H, dd, J=3Hz, 1Hz), 3.82 (1H, d, J=llHz), 3.89 (1H, d, J=9Hz) 3.79 (3H, 3.53 (1H, dd, J=lOHz, 3H1z), 3.44 (2H, in), 3.30 (1H, in), 3.20-2.95 (5H, in), 2.80 (1H, d, J=l4Hz), 1.43 (3H, in), 1.23 (3H, in), 1.08 (2H, mn), 0.87 (3H. t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DC I/NH 3 m/e 507 AnaI.calc. for C 30

H

3 8N20,5 0.75 H20: C, 69.28; H, 7.65; N, 5.39. Found: C, 69.11; H, 7.33; N, 5.32.

Examlole 141 trans. trans-i N- Di(n-butfla m inocarbonyim ethyl')-2- (4-m ethoLxy~hefl)f-4- (6ben zo-2 .3-dihyd rofu ranyl) gvrrolidi ne-3-ca rboxylic acid The title compound was prepared by catalytic hydrogenation of the compound resulting from Example 140 (4 atmospheres of H 2 in AcOH, followed by preparative hp!c). 1 H NMR (300 MHz, CDC13) 8 7.40 (2H, d, J=8Hz), 7.16 (OH, 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 (1 H, mn), 3.30-2.90 (8H, in), 1.40 (2H, in), 1.29 (3H, in), 1.05 (2H, in), 0.92 (3H, t, J=7H1z), 0.82 (3H, t, J=7Hz). MS (DCI/NH 3 Wne 509 Anal.calc. for C 30

H

4 oN205 0.85 TEA: C, 62.88; H, 6.80; N, 4.63. Found: C, 63.04; H, 6.66; N, 4.60.

WO 99/06397 PCT/US98/15479 00 -165- Eamgle 142 -tra-ns. trans- 1 (-ehlNDoyaioabnlmlhl--4mto indanyl~yrrolidine-3-carboXalic acid 00 Eamle AA I 00 lndane-5-carboxaldehyde was prepared by formylation of indane Sunder the conditions described for 2,3-dihydrobenzofurafl in Example 1 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 1 as a white solid. The aldimine (2.65 g) was suspended in water (6 mL), and treated with 4 N~ hydrochloric dioxane (10 mL). The mixture was boiled for 1 hour, cooled to room temperature, and poured into ether.

The organic solution was dried over 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 IC at 0.9 mm Hg.

Examl~le- 142 trans. trans- 1 (-ehlNpo~lr~ncrovmty)2(-rhxpey)4(indanyl~nrrolidifle-3-carboXyliC 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, CDCI3) (minor rotamer) 8 7.25-7.1 in), 6.78 (2H, d, J=8Hz), 3.89 (1H, d, J=BHz), 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=BHz), 1.48 (2H, septet, J=7Hz), 0.83 (0.73) (3H, t, J=7Hz). MS (DCI/NH3) mn/e 451 473 Analcalc. for 0 27

H

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

WO 99106397 PCTIUS98/15479 00 -166trans. trans- I- (N-Methyl-N-ProOylamiflocarboflylm ethyl)--4mtOy~elf--6 indolyl)p2yrrolidine.3-carboxylic 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. 1H NMR (300 MHz, CDCI3) (minor rotamer) 8 8.43 (11-H, brs), (N7.57 (11H, d, J=8H-z), 7.43 (1 H 7.31 dd, J=6Hz, 3Hz), 7.22 (1IH, d, 00 J=8Hz), 7.1 t, J=3H-z), 6.78 (2H,dd, J=6Hz, 3Hz), 6.45 (1H, in), 3.93 S(1H1, dd, J=6Hz, 3H-z), 3.80 (1H, mn), 3.73 3.60-2.90 (6H1, in), 2.86 S(2.82) (3H1, 1.47 (2H, septet, J=7H-z), 0.83 (0.731. (3H1, t, J=7H1z).

MS

(DCI/NH3) m/e 450 Anat.calc. for C 26 H131 N304 0.75 H20: C, 67.44; H, 7.07; N, 9.07. Found: C, 67.42; H, 7.09; N, 8.91.

Eampil144 trans. trans-i 4 (N-Methyl-N-propylamiflocarbonlviethyl)-2(4methoxYhenvI'- 4 3 .4-difluorolheflyl~Dvrrglidife3-arboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobeflzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) (minor rotamer) 8 7.60-7.3 (4H1, 7.13 (1 H, q, J=9H-z), 6.90 (2H, d, J=8H1z), 3.90 (1 H, in), 3.79 (3H, 3.60-2.95 (611, in), 2.92 (2.78) (3H1, 1.55 septet, J=7H1z), 0.88 (0.73) (3H4, t, J=7Hz). MS (DCI/NH3) mWe 447 Anal.calc. for

C

24 H28F2N2O4 1.80 H 2 0: C, 60.19; H, 6.65; N, 5.85. Found: C, 60.13;

H,

6.34; N, 5.84.

Eample 145 trans, trans:-1 -Methyl-N gropylam inocarbonylmethyfl=2-(4-methoxyihenyl)- 4 (oheny'pyrrolidile-3-carbOxy~ic acild The title compound was prepared by the procedures described in Examples 1 and 49 substituting benzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDC13) (minor rotainer) 8 7.53 d, J=6H1z), 7.40-7.20 (3H1, in), 6.88 (211, d, J=8H1z), 3.90 (1H, in), 3.79 (3H, -3.70- 2.95 (8H, in), 2.90 (2.79) (3H, 1.50 (2H, sept, J=7Hz), 0.87 (0.72) (3H1, t, J=7Hz). MS (DCI/NH3) m/e 411 AnaI.calc. for C 24

H

3 ON2O4 2.00 H20: C, 64.55; H, 7.67; N, 6.27. Found: 0, 64.37; H, 7.43; N. 6.29.

WO 99/06397 PCT/US98/15479 0O9/697PTU98I57 00 -167- Example 146 __tran s. trans-i 1 (N-MethylNpro~ylami-OcarbonylmethYl)-2(4methoxwhenyl) 4 4 hyd roxyn~henyfloyrrol idine-3-carboXylic acid 00 The title compound was prepared by the procedures described in.

~'Examples 1 and 49 substituting 4-hydroxybenzaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDC1 3 -CD3OD) (minor rotamner) 8 7.35 N- (2H, d, J=BHz), 7.28 (2H, dd, J=7Hz, 3Hz), 6.90 (2H, dd, J=7Hz, 3Hz), 6.89 00 S(2H, d, J=BHz), 3.81 (3H, 3.65 (1H, d, J=BHz), 3.70-3.00 (8H, in), 2.92 S(2.83) (3H, 1.50 (2H, septet, J=7Hz), 0.87 (3H, t, J=7Hz). MS (DCI/N .H3) m/e 427 AnaI.calc. for C 24

H

3 0N205 -1.00 H 2 0: C, 64.85; H, 7.26; N, 6.30. Found: C, 64.82; H, 7.39; N, 6.46.

Exam Die 147 trans.trans-1 Mehl -rpla oaroymty)2 4mehxgey)4 (2 .4-dimethoxyghenlflDrrolidine3-carboxyitc acid The title compound was prepared by the procedures described in Examples I and 49 substituting 2,4-dimethoxyberIzaldehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDC1 3 -CD30D) (minor rotamer) 8 7.61 (1H, d, J=8Hz), 7.30 (2H, d, J=8Hz), 6.82 (2H, d, J=BHz), 6.55 (1H, 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 (DCI/NH3) We 471 Anal.calc. for C 26 H34N206 0.75 H20: C, 64.51; H, 7.39; N, 5.79. Found: C, 64.65; H, 7.07; N, 5.75.

-Exmi~l 14 trans. trans-i1 N-EDi(n-tutyl)amf inocarbonytinthyl)2(4-methoxyohenyl) 4 5 benzo-2 3dihydrofurnylyrrolidine3acarboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,3-dihydrobeflzofu carboxaldehyde for. piperonal in Example 49A. 1 H NMR (300 MHz, CDC13) 8 7.31 (2H, d, J=BHz), 7.27 (1H, d, J=2Hz), 7.18 (1H, dd, J=7Hz, 3Hz), 6.86 (2H, d, J=8Hz), 6.72 (1H, d, J=BHz), 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 O1H, d, J=l4Hz), 1.43 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 (3H, WO 99/06397 PCT/US98/15479 00 -168t, J=7Hz), 0.81 (3H. t. J=7Hz). MS (DCI/NH3) m/e 509 Anal.calc.

N- for C 30

H

4 ON205 0.25 H 2 0: C, 70.22; H, 7.95; N, 5.46. Found: C, 70.2.1; H.

7.92; N, 5.36.

00 a JA trans, trans-i N-Di(n-butyflaminocarboflm ethyfl-2-(4-m ethoxyphenyfl-4-(4methoxy~henylovrrlidile-3-carboxyic acid 00 The title compound was prepared by the procedures described in 0 Examples 1 and 49- substituting 4-methoxybeflzaldehyde for piperonal in Example 49A. I H NMR (300 MHz, CDCI3) 8 7.38 (219, d, J=BHz), 7.30 (2H, d, J=8Hz), 6.87 (4H, dd, J=7Hz, 3Hz), 3.78 (3H, 3.76 (3H, 3.63 (1H, in), 3.50-3.20 (4H, in), 3.15-2.90 (5H, in), 2.78 (1H, d, J=l4Hz), 1.43 (3H, mn), 1.27 (3H, in), 1.09 (2H, in), 0.87 (3H, t, J=7Hz), 0.81 (3H, t, J=7Hz). MS (DCI/NH3) m/e 497 Anal.calc. for C 29

H

4 0N2O5S: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.78; H, 8.10; N, 5.54.

Example 150 trans. trans-i1 .N-Di(n-butl~al1inocarbonvlmethyl)-2-(4.inethoxyphenyl- 4 3 4 dif Iuoroghen yl)pyrro lid i n-3-cgrboxyl ic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3,4-difluorobeflzaldehYde for piperonal in Example 49A. I H NMR (300 MHz, CDCI3) 8 7.35 (1H, in), 7.30 (2H, d, J=8Hz), 7.20-7.00 (2H, mn), 6.87 (2H, d, J=8Hz), 3.78 (3H, 3.79 (1H, in), 3.62 (1H, mn), 3.50-3.30 (3H, in), 3.23 (1H, in), 3.15-2.90 (4H, mn), 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.08 (2H, mn), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH3) Wne 503 Anal.calc.

for C 28

H

36

F

2 N204- 1 H 2 0: C, 64.60; H, 7.36; N, 5.38. Found: C, 64.59; H, 7.20; N, 5.35.

Example 151 trans. trans-i1 N-Di (n-butyl) am inocarbonylinethYl)-2(4-iethoxVlhenYl4( 2 .4dim ethoxynhenfloYfDrrlidine3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 2,4-dimethoxybenzaidehyde for piperonal in Example 49A. 1 H NMVR (300 MHz, CDCI 3 8 7.37 (2H, d, J=8Hz), 7.20 (OH, d, J=8Hz), 6.92 (2H, d, J=8Hz), 6.60 (1H, d, J=3Hz), WO 99/06397 PCT/US98/15479 00 -169- S6.49 (1 H, dd, J=6Hz, 2Hz), 5.35 (1lH, d, J=8Hz), 4.20 (3H, in), 4.10 (3H, s), 3.83 (3H, 3.81 (3H, 3.75 (3H, in), 3.17 (2H, hep, J=7Hz), 3.05 (2H, St, J=7Hz), 1.30 (4H, in), 1.07 (4H, in), 0.87 (3H, t, J=7Hz), 0.80 (3H. t, J=7Hz). MS (DCI/NH 3 m/e 527 AnaI.calc. for C 30

H

42

N

2 0 6 1.30 00 TFA: C, 58.02; H, 6.47; N, 4.15. Found: C, 57.92; H, 6.43; N, 4.07.

Exmple 152 CItrans. trans-i1 N- Di (n-b uty) am in oca rb onylm ethyl)-2- phenl-4- 1.3-ben zodioxo 00 0 yl~pyrrolidine-3-carbgxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B.

1 H NMR (300 MHz, CDCI3) 8 7.50-7.25 (5H, in), 7.04 (1 H, 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, in), 3.42 (3H, in), 3.27 (2H, in), 3.20-2.90( (5H, in), 2.81 (1H, d, J=l4Hz), 1.43 (2H, in), 1.27 (4H, in), 1.05 (2H, in), 0.85 (3H, t, J=7Hz), 0.80 (3H, t, J=7Hz). MS (DCI/NH 3 mle 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.

trans. trans-i1- N-Di(n-butvl amin ocarbonylmethvfl2-1henlI4(5belzo- 2 .3dihydrofuranVF)Dyrrolidile-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl benzoylacetate in Example 49B and 2,3-dihydrobenzofuran-5-carboxaldehyde for piperonal in Example 49A. liH NMR (300 MHz, CDC13) 7.53 (2H, in), 7.40 (4H, in), 7.13 (IH, dd, J=7Hz, 3Hz), 6.72 (1H, d, J=8Hz), 5.40 (1H, d, J=lOHz), 4.56 (2H, t, J=8Hz), 4.18 (1H, d, J=l4Hz), 4.07 (2H, in), 3.79 (2H, in),.3.48 (1H, d, J=1l4Hz), 3.35 (1 H, 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 gH 3 8N2O4 1.10 TFA: C, 62.04; H, 6.52; N, 4.64. Found: C, 61.89; H, 6.44; N, 4.57.

WO 99/06397 PCT/US98/15479 00 -170- Exampl154 trans. trans- N-Di (n-butyl~am inocarbonylmethyl)2(4tbutylpheyl)- 4 (Sbnzo- 2. 3-dihydrofuranyl)pyrrolidile-3-carb6Xylic acid The title compound was prepared by the procedures described in 00 Examples 1 and 49 substituting t-butyl benzoylacetate, prepared by the method of Krapcho et al.,.Org. Syn. 47:20 (1967) starting from 4-tbutylaCetopheflofe, in Example 49B and 2,3-dihydrobelzofurafl-5- 00 carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.60-7.30 (6H, in), 6.90 (1H, in), 4.50 (2H, mn), 3.95 (iH, in), 3.85-2.95 (11H, mn), 2.90 (1H, d, J=l4Hz), 1-.58 (2H, in), 1,50 (7H, mn), 1.41 (6H, 1.10 (2H, mn), 1.00 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). MS (DCI/NH3) mWe 535 Anal.calc. for C 33

H

4 6N204 -0.25 H 2 0: C, 73.50; H, 8.69; N, 5.19. Found: C, 73.57; H, 8.58; N, 5.14.

trans. trans-2-(N N-inbjlai mehgpey -4 fluoroghenlflgrlidifle-3carbo(ylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 4-fluorobenzaldehyde for piperonal in Example 49A. IH NMR (300 MHz, CDC13) 6 7.50 (1H, in), 7.42 (1H, dd, J=7Hz, 3Hz), 7.36 (2H, d, J=8Hz), 7.01 (3H, t, J=8Hz), 6.87 (1H, d, J=BHz), 3.83 (1 H, mn), 3.8 (3H, 3.67 (1IH, in), 3.47 (3H, in), 3.30-2.90 (5H, in), 2.82 (1H, d, J=l4Hz), 1.43 (2H, in), 1.28 (4H, in), 1.08 (2H, in), 0.90 (3H, t, J=7Hz), 0.82 (3H, t, J=7Hz). MS (DCI/NH3) Wne 485 Anal.calc.

for C 28

H

3 7FN204: C, 69.40; H, 7.70; N, 5.78. Found: C, 69.03;, H, 8.00; N, 5.74.

Exmple156 trans, trans-i1 N- Di(n-butyflamfiloca rbgnylmhy'-(3f!l 4 3bnopX- 5.yl~gyrrolidile-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting D3-oxo-3-furanpropioflate in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 7.41 (2H1, in), 6.97 (1 H, d, J=3Hz), 6.85 (1 H, dd, J=7Hz, 3Hz), 6.72 (1 H, d, J=BHz), 6.42 (1 H, 5.94 (11-I, d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.90 (1 H, in), 3.70-3.25 (5H, in), 3.20-2.90 (4H, in), 2.85 (1H, d, J=l4Hz), 1.43 (2H, mn), 1.40-1.05 (6H, in), 0.90 (6H, WO 99/06397 PCT/US98/15479 00 -171in).MS (DCI/NH3) mWe 471 AnaI.calc. for C 26

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.

00 trans. trans-i1 .N-Di (n-butyl)am inocarbonlmethyl-2- (isogropl 4 .3- __ben zod ioxoI-5-Myfl1yrro id ie- 3-ca rboXyic acid The title compound was prepared by the procedures described in c'IExamples 1 and 49 substituting ethyl isobutyrylacetate in Example 49B3' 00 0 1 H NMR (300 MHz, CDCI3) 8 6.85 (1H, d, J=2Hz), 6.76 (1H, dd, J=6Hz, 2Hz), c~6.71 (OH, d, J=BHz), 5.92 (2H, 3.75 (1H, d, J=141-z), 3.66 (1H, q, J=7Hz), 3.42 (3H, in), 3.25 (3H, in), 3.11 2.83 (1H, t, J=7Hz), 1.88 (I H, in), 1.55 (4H, in), 1.32 (4H, in), 0.92 (12H, in). MS (DCI/NH3) mWe 447 Anal.calc. for C 25

H

38 N 205 0.50 H 2 0: C, 65.91; H, 8.63; N, 6.15. Found: C, 66.07; H. 8.10; N, 6.03.

trans. trans-i1 N-inbtlaioabnlehy)2(- ~ypey)4(.3benzdiool.5yl)yrrlidile-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 4-t-butylbenzoylacetate, prepared by the method of Krapcho et al., Org. Syn. 47: 20 (1967) starting with 4t-butylacetopheflone), in Example 49B. IH NMR (300 MHz, CDCI 3 8 7.32 (4H, d, J=3Hz), 7.04 (1H, d, J=2Hz), 6.87 (1H, dd, J=8Hz, 3Hz), 6.74 (1H, d, J=9Hz), 5.94 (1H, d, J=4Hz), 5.92 (IH, d, J=4Hz), 3.77 (1H, d, J=l4Hz), 3.65-3.25 (5H, mn), 3.15-2.85 (4H, in), 2.73 (1H, d, J=l4Hz), 1.45 (2H, in), 1.29 (13H, 1.00 (2H, in), 0.86 (3H, t, J=7Hz), 0.76 (3H, t, J=7Hz). MS (DCIINH3) m/e 537 Anal.calc. for C 32

H

44 N206: C, 71.61; H, 8.26; N, 5.22. Found: C, 71.43; H, 8.09; N, 5.11.

30Exml15 trans. trans-i -(N.N-inbt 2 .3-dihydrfurayl~prrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples I and 49 substituting ethyl isobutyryl acetate in Example 49B and 2,3-dihyd robenzof u ran-5- carboxal dehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCI3) 8 7.30 (1H, 7.13 (1H, dd, J=7Hz, 2Hz), WO 99/06397 PCTIUS98/15479 00 -172- S6.82 (1 H, d, J=8Hz), 4.68 (2H, t, J=8Hz), 4.48 (1 H, 3.19 (3H, in), 3.80 (3H, mn), 3.48 (2H, in), 3.3 (5H, in), 2.41 (1 H, mn), 1.65 (4H, mn), 1.44 (4H, r 1.21 (3H, d, J=5Hz), 1.17 (3H, d, J=5Hz), 1.05 (6H, mn). MS (DCIINH3) m/e 445 AnaI.calc. for C 26

H

40 N204 -1.2 TFA: C, 58.67; H, 7.14; 00 N, 4.8.2 Found: C, 58.54; H, 7.25; N. 4.74.

Example 00 trans, trans-i N.Di(n-butyl)im inocarbonylmethy)2(alti4-methoxyclohexyl)- 1.3-benzodioxol5y~Dyrrolidifle-3-caboxylic acid Example160A syn and anti Ethyl 4methozycyclohexafloylacetate Syn, anti-4-Methoxycyclohexafle carboxylic acid (5.00 g, 31.6 mmol) and carbonyldiimidazole (6.15 g, 37.9 mmol, 1.2 eq) were stirred in anhydrous tetrahydrofuran (50 mL) for 6 hours at room temperature.

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

The solvents were removed under reduced pressure, and the residue was taken up in chloroform/water. The organic phase washed with potassium bisulf ate, 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 methoxycyclohexyl P-keto esters were obtained. The solvents were removed under reduced pressure to yield the trans-4-methoxycycohexyl 0-keto ester (914 mg) as a colorless oil and the cis 4inethoxycyclohexyl 53 keto ester (1.07 g) as a colorless oil.

Examle160 trans, trans-i1 N-Di(fl-butyflpmiflOrboflylmethyl)- 2 -(anti-4-methoxycvclohexytflbnoixl5y~yroiie3croyi acid The title compound was prepared by the procedures described in Fxamples 1 and 49 substituting the anti-compound resulting from WO 99/06397 PCT/US98/15479 00 -173- SExample 160A in Example 49B. 1 H NMR (300 MHz, CDCI 3 8 6.84 (1 H. d, SJ=2Hz), 6.76 (1H, dd, J=7Hz, 2H-z), 6.61 (1H, d, J=8Hz), 5.92 3.69 Ni (2H, in), 3.50-3.27 (5H, in), 3.26 (3H, 3.25-3.00 (3H1, mn), 2.88 (1H, mn), 1.95 (2H, mn), 1.62 (7H, mn), 1.33 (9H, in), 0.97 (3H, t, J=7Hz), 0.92 (3H, t, 00J=7Hz). MS (DCI/NH3) W/e 517 AnaI.calc. for C 29 H44N2O6 0.50 C, H20: C, 66.26; H, 8.63; N, 5.33. Found: C, 66.27; H, 8.50;, N, 5.13.

Examl~ig- 1 0 0 1.3-benzodioxol5-Vfl)1yrrolidifle-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting the syn-compound resulting from Example 160A in Example 49B. 1 H NMR (300 MHz, CDCI3) 8 6.84 (1H, d, J=2H-z), 6.77 (1H, dd, J=6Hz, 2H1z), 6.61 (1H, d, J=8H-z), 5.92 (2H, 3.65 (2H1, in), 3.42 (2H1, in), 3.32 3.30-3.00 (611, in), 2.82 (1 H, mn), 2.10 in), 1.83 (2H1, in), 1.52 (6H, in), 1.33 (4H, mn), 1.20-1.00 (4H, in), 0.96 (3H, t, J=7H1z), 0.91 (3H, t, J=7Hz). MS (DCIINH3) Wne 517 Anal.calc. for C 29

H

44 N206 0.30 H 2 0: C, 66.72; H, 8.61; N, 5.37. Found: C, 66.76; H, 8.65; N, 5.28.

Examgke 16 trans, trans-i1 N-Di(n-butyflainocrbonflmlethyl- 2 .4-di(5-beflzo-2.3dihydrofu ranvlllgyrrolidifle-3-carbOXy11ic acid Example 162A 5-Acetyl-2. 3-dihydroben zof u ran To a 0 OC solution of acetyl chloride (1.64. mL, 23.0 inmol, 1.3 equivalents) in inethylene chloride (30 ml-) was added stannic chloride (2.49 inL, 21.3 minol, 1.2 equivalents), maintaining the temperature below 5 OC. The solution was stirred 15 minutes at 0 OC, and then a solution of 2,3-dihydrofuran (2.00 inL, 17.7 minol) in methylene chloride inL was added dropwise while maintaining the temperature below 8 The dark red solution was stirred 1 hour at 2 0 C and then poured into 50 mL of ice water. The reaction was stirred an additional minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium WO 99/06397 PCT/US98/15479 00 -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.

00 trans-I -(N.N-Di(nbutylaminocarbonylmethyl)-2.4di(-benzo 2 3 dihydrofuralyloyrrolidile-3-carboXYlic acid 00 The title compound was prepared by the procedures described in CIExamples I and 49 substituting the compound resulting from Example 162A in Example 49B and 2.3-dihydrobenzofuraf-5-carboxaldehyde for piperonal in Example 49A. 1 H NMR (300 MHz, CDCi3) 8 7.43 7.38 (1 H, 7.06 in), 6.75 (1 H, d, J=6H-z), 6.70 (1 H, d, J=6H-z), 5.40 (1 H, d, J=9Hz), 4.58 (4H1, q, J=7H-z), 4.16 (11H, d, J=l4Hz), 4.09 in), 3.82 (2H, in), 3.57 (1H, d, J=l4H-z), 3.38 (11H, in), 3.30-3.05 in), 2.95 (2H-, q, J=6H-z), 1.50 (2H, in), 1.30 in), 1.15 in), 0.94 t. J=7H-z), 0.83 (3H, t, J=7H-z). MS (DCI/NH 3 mWe 521 Anal.calc. for

C

3 11- 4 0N205 1.25 TFA: C, 60.67; H, 6.27; N, 4.22. Found: C, 60.49; H, 6.18; N, 4.13.

trans. trans-i1 .N-Di (n-butyl~am inocarbonylmethyl2(3f uryl)4(5benzo- 23 dihydrofurany)pyrrolidifle-3-carbgxYic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl f3-oxo-3-f uran propionate in Example 49B and 2 ,3-dihyd robenzof uran5carboxald ehyde for piperonal in Example 49A. 1H NMR (300 MHz, CDC1 3 8 7.42 (1IH, in), 7.38 (1H, in), 7.13 7.16 (1H1, dd, J=7Hz, 3Hz), 6.70 d, J=8H-z), 6.41 (1H, in), 4.57 t, J=7H-z), 3.95 (1H, d, J=8H-z), 3.63 (1H1, in), 3.55 (1H, d, J=14), 3.50-3.25 (4H, mn), 3.18 (2H, t, J=6Hz), 3.15-2.95 (3H, in), 2.87 (1H, d.

J=l4H-z), 1.45 in), 1.35-1.10 (4H, in), 0.85 (6H, in). MS (DCIINH3) m/e 469 AnaI.calc. for C 27 H36N205 -0.25 H20: C, 68.55; H, 7.78; N, 5.92. Found: C, 68.62; H, 7.68; N, 5.82.

WO 99/06397 PCT/US99/1 5479 00 -175- Examp1l164 trans. trans-i N- Di(n -butyl) am in ocarbolymethyl)2- 4-m ethoxyghenyI) 4 3 f luorophenyl~yrroidile3-carboxyliC -acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3.fluorobenzenecarboxaldehYde for 00 piperonal in Example 49A. 1 H NMR (300 MHz, CDC13) 5 7.30 (2H1, d.

SJ=8Hz), 7.22 (2H, in), 6.91 (1KH, in), 6.86 (2H, d, J=8Hz), 3.79 (1 H, in), 0 3.78 (3H, 3.68. (1 H, in), *3.55-3.37 (3H, in), 3.29 (1 H, mn), 3.15-2.90 00 (5H, in), 2.78 (1H, d, J=l4Hz), 1.43 (2H, in), 1.25 (4H, in), 1.07 (2H, mn), S0.87 (3H, t, J=7Hz), 0.80 (3H1, t, J=7Hz). MS (DCILNH3) mle 485 SAnal.calc. for C 2 1IH 37 FN204 -0.25 H120: C, 68.76; H, 7.73; N, 5.73. Found: C, 68.87; H, 7.69; N, 5.67.

1 trans. trans-i N-Di(n-butyl~am inocarbonylmethyl')-2-(4--methoXylhenl)b 4 3 12yridyl)1oyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting 3-pyridinecarboxaldehyde for piperoflal in Example 49A. The nitro styrene was prepared by the method of 2 Bourguignon ,et al., Can. J. Chem. 63: 2354 (1985). IH NMR (300 MHz, CDC13) 8 8.82 (1H, bs), 8.73 (1H1, bd, J=9Hz), 8.62 (1H1, bd, J=7Hz), 7.78 (1H1, bdd, J=9Hz, 3Hz), 7.38 (2H. d, J=lOHz), 6.90 (2H1, d, J=IOHz), 4.39 (1H1, d, J=l2Hz), 3.95 (1H1, in), 3.80 (3H1, 3.79 (1H1, in), 3.68 (1H1, d, J=l8Hz), 3.50-3.30 (3H, in), 3.25-2.90 (6H1, in), 1.47 (2H1, in), 1.31 (4H1, in), 1.20 (2H, in), 0.92 (3H1, t, J=7Hz), 0.83 (3H, t, J=7Hz). MS (DCIINH3) Wne 468 Anal.calc. for C 27 H37N3Q4 1.65 TFA: C, 55.50; H, 5.94; N, 6.41. Found: C, 55.53; H, 5.90; N, 6.27.

Exaaple 6 trans. trans-i 1 (N.N-Di (n-butyl)am in ocarbonvlm ethyl)-2-(2-f1uorophenyt)- 4 .3enzodioxol-5-yl)Dyrrolidine3-carboxylic acid The title compound was prepared by the procedures described in Examples 1 and 49 substituting ethyl 2-f luorobenzoyl acetate in Example 49B. 1H1 NMR (300 MHz, CDC13) 8 7.52 (1H1, dt, J=7Hz, 3Hz), 7.25 (11H, in), .7.13 (11H, dt, J=7Hz, 3Hz), 7.02 (211. in), 6.88 (1IH, dd, J=7Hz, 3Hz), 6.73 (111, d, J=BHz), 5.93 (111, d, j=4Hz), 5.92 (111, d, J=4Hz), 4.25 (1H, d, J=9Hz), 3.68 (1H1, in), 3.42 (3H1, in), 3.39 (111, in), 3.20-2.95 (4H, WO 99/06397 PCT/US98/15479 00 -176in), 2.91 (1H, d, J=l4Hz), 1.45 (3H, in), 1.26 (3H, in), 1.08 (2H, in), 0.87 N (3H, t, J=7Hz), 0.81 (3H1, t, J=7Hz). MS (DCIINH 3 mWe 499 Analcaic. for C 28

H

35 FN205 .0.25 H 2 0: C, 66.85; H, 7.11; N, 5.57. Found: C, 66.51; H, 6.67; N, 5.18.

00 Example 67 trans. trans- 1- N-DI(n-butyl)am inocarbonylm ethyfl-2-(3-fluoropheflyl)-4-( 1.3- 00 benzodioxol-5-yl) pyrrolidine-3-carboxylic acid The title compound was prepared by the procedures described In SExamples 1 and 49 substituting ethyl 34fluorobenzoyl acetate in Example 49B. 1H NMR (300 MHz, CDCI3) 8 7.38 (1 H, mn), 7.18 (1 H, d, J=7Hz), 7.15 (1H, in), 7.00 (1H, d, J=2Hz), 6.95 (1H, mn), 6.86 (1H, dd, J=7Hz, 2Hz), 6.75 (IH1, d, J=8Hz), 5.93 d, J=4Hz), 5.92 (11-1 d, J=41-z), 3.94 (1H, d, J=l4Hz), 3.63 (1H, mn), 3.42 (3H, mn), 3.35-2.95 (5H, in), 2.87 (1H, d, J=l4Hz), 1.44 (3H, in), 1.27 (3H, in), 1.10 (2H, in), 0.88 (3H, t, J=7Hz), 0.81 (3H, t, J=7.Hz). MS (DCI/NH3) in/e 499 Anal.calc.

for C 28

H

35

FN

2 05: C, 67.45; H, 7.08; N, 5.62. Found: C, 67.32; H, 7.05; N, 5.40.

Example 16 trans. trans-i N-Di(n-butyflaminoghenl)-2-( 4 -m ethoxyghenyl)-4-( 1.3pyrrolidine-3-carboxylic acid 4-Nitro-1 -fluorobenzefle, ethyl trans, trans-2- (4methoxyphenyl)-4-(l ,3-benzodioxol-5-yl)-pyrrolidine3-carboxylate (the compound resulting from Example 6A), and diisopropylethylaine are heated in dioxane to give ethyl trans, trans-2-(4-nethoxYPhenYl)- 4 (1 ,3-benzodioxol-5-yl)-l -nitro ph enyl) -pyrrol Idi ne-3-carbo xyl ate.

The nitro compound is hydrogenated to give the corresponding aininophenyl compound. The aminophenyl compound is reacted with butyraldehyde and sodium cyanoborohydride according to the method of Borch, J. Am Chein. Soc. 93: 2897 (1971) to give the corresponding

N,N-

dibutylaininophenyl compound. Hydrolysis with sodium hydroxide using the method of Example 1D affords the title compound.

WO 99/06397 PCT/US98/15479 00 -177- Example169 trans. trans-i1 N-Dibutylaminoi2Yriml idin-4-yl)-2-(4-mthoXhfl)-4-( 1.3hen zodioxol5-Ppyrro id i ne-3-carboxylic- acid 2-(Dibutylamino)-4-chloropyrimidifle is prepared from 2,4dichloropyrimidifle according to the method of Gershon, J. Heterocyclic 00 Chem. 24: 205 (1987) and reacted with ethyl trans, trans-2-( 4 methoxypheflyl)-4-(1 ,3-benzodioxol5y)pyrrolidie3carboxylate (the compound resulting from Example 6A) and diisoproplyethylamirle in 00 dioxane with heating to give the intermediate ethyl ester, which is Shydrolyzed with sodium hydroxide using the methodi of Example I D to Sthe title compound.

Examples.17-266 Using the procedures described in Examples 1, 4, 5, 7, 8 and 9 and Scheme X, the following compounds can be prepared.

Ex. No. Name 170 trans, trans-2-(4-Methoxyphenyl) 4 (l 93- 1- (isopropyl ami nocarbonyl methyl) pyrrol idin e- 3 carboxylic acid; 171 trns tas2(-ehxpny)41,3be nzodi oxol- 5-yl)- 1 -(ethylamiflocarbotnylm ethyl)pyrrolidine-3-carboxYlic acid; 172 trns tas2(-ehxpny)41,3benzodioxol-5-y)l1 methylpropylaminocarbonylmethyl)pyrrolidine- 3 carboxylic acid; 173 trns trn--4Mtoyhnl 9-13benzodioxol-5-yl)-l1 (phenylamiflocarbonylmethyl)pyrrolidine-3-carboxylic acid; 174 trns 9rn--4Mtoyhnl--13benzo di oxol-5yl)l 1 (pipe ridi nyl carbon~yl methyl)pyrrolidine-3-carboxylic acid; WO 99/06397 WO 9906397PCT/US98/1 5479 00 -178- 1 75 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yi)-1 ci(propyl am inocarbonyl) ethyl)-pyrrol idi ne-3carboxylic acid; 00 176 trans, tr ans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1-(a- (propylaminocarbonyl)benzyl)-pyrroiidine-3carboxylic acid; 00 177 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3ben zodioxol-5-yi)-1 -(bisc-i (propylaminocarbonyl)methyl)-pyrrolidine-3carboxylic acid; 178 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3benzodioxol-5-yI)-1 (propylaminocarbonyl)ethyl)-pyrrolidine-3carboxylic acid; 179 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yt)-1 ropytaminosuIf onyl methyl)pyrrotidine-3-carboxylic acid; 180 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3- 1 -(2-phenethyl)-pyrrolidine-3carboxylic acid; 1 81 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yI)-1 -(pentanoylm ethyl) pyrrolidine-3-carboxylic acid; 182 trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3- 1 -(ben zoylmethyl)-pyrrolidine- 3-carboxylic acid; 183 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yi)-1 -(hexyl)-pyrrolidine-3carboxylic acid; 184 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yi)-1 -(2-hexynyt)-pyrrolidine-3carboxylic acid; 1 85 trans, trans-2-(4-Methoxypheflyl)-4-( 1,3benzodioxol-5-yl)-1 -(propoxymethylcarbonylpyrroli dine- 3-carboxyl ic acid; WO 99/06397 PCT/US98/15479 -179- 00 186 trans, trans-2-(4-M ethoxyphenyl)-4-( 1,3be nzodioxol-5-yI)- 1 -(phenylacetyl)-pyrrolidifle-3carboxylic acid; 187 trans, trans-2-(4-Methoxypheflyl)-4-( 1,3benzodioxol-5-yI)-1 -(anilinylcarbonyl)- 00 pyrrolidine-3-carboxylic acid; 188 trans, trans-2-(4-Methoxypheflyl)-4-(1 13benzodioxol-5-yl)-1 -(2-acetylaminoethyl)- 00 pyrrolidine-3-carboxylic acid; 180rn0rn-2(-ehxpefy)4(13 benzodioxol-5-y)-1 -(2-pheloxyethyI)-pyrrolidile- 3-carboxylic acid; 190 trans, trans-2-(4-Methoxypheflyl)-4-(l ,3benzodioxol-5-yI)-l1 (2-benzodioxanylmethyl)pyrrolidine-3-carboxylic acid; 191 trans, trans-2-(4-MethoxypheflY) 4 (l.

3 benzodioxol-5-yI)-1 -(2-tetrahyd rofuraflylmiethyl)pyrrolidine-3-carboxylic acid; 192 trans, trans-2-(4-MethoxyphelY) 4 1,3benzodioxol-5-yI)-1 (propylaminocarboflylamliflo)etheli)-pyrrolidine- 3 carboxylic acid; 193 trans, trans-2-(4-Methoxypheflyl) 4 (l 3benzodioxol-5-yi)-1 (p ropyl ami nocarb oylamifno) ethyl) pyrrolidifle- 3 carboxylic acid; 1 94 trans, trans-2-(4-Methoxyphefl)-4-( 1,3- 1-(3-oxohex-1 -enyl)pyrrolidine-3-carboxylic acid; 1 95 trans, trans-2-(2,4-Di meth oxypheflyl) 4 (l 3benzodioxol-5-yI)-l1 (propylaminocarboflmethyI)pyrrolidine-3-carboxylic acid; 1 96 trans, trans-2-(2-Carboxy-4-methoxypheflyl)- 4 (1 ,3-benzodioxol-5-yl)-1 (propylaminocarboflylmethyl)-pyrrolidifle- 3 carboxylic acid; WO 99/06397 WO 9906397PCTIUS98/15479 00 -180- 197 trans, trans-2-(2-Aminocarbonyl-4methoxyphenyl)-4-( 1,3-benzodioxol-5-yi)- 1 ci(p ropylami nocarbo nyl methyl) -pyrrol idine-3 carboxylic acid; 00 198 trans, trans-2-(2-Methanesulf onamido-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yI)-1 (p ropyl amin ocarbo nyl methyl) -pyrrol idine-3carboxylic acid; 00 199 trans, trans-2-(2-Aminocarbonylmethoxy-4methoxyphenyl)-4-( 1,3-benzodioxol-5,yI)-1 (propylamin ocarbo nyl methyl) -pyrroIi d ine-3carboxylic acid; 200 trans, trans-2- (2 -Met hoxyethoxy-4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1- (p ropylami nocarbonyl methyl) -pyrrol idine-3carboxylic acid; 201 trans, trans-2-(2-Carboxymethoxy-4methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)- 1- (propylaminocarbonyl methyl)-pyrrolidine-3carboxylic acid; 202 trans, trans-2-(4-Methoxy-2tetrazolylmethoxyphenyl)-4-( 1,3-benzodioxol-5yI)-l -(propylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 203 trans, trans-2-(2-AIlyloxy-4-methoxyphenyl)-4- (1 ,3-benzodioxol-5-yI)-1 (p ropylami nocarbonyl methyl) -pyrrol idi ne-3carboxylic acid; 204 trans, trans 2,4-Bis (4 -meth oxyphenyl) -1 (p ropyla m in oc arbo nyl m et hyl) -pyrrol id in e-3 carboxylic acid; 205 trans, trans 2,4- Bis( 1 ,3 -b e nzod io xol- 5-yI) -1 (p ro pyl am in ocarb on yl met hyt1) -pyrrolIi d ine -3 carboxylic acid; WO 99/06397 PCT/US98/15479 00 -181- 206 trans, trans -2-(4-Methoxyphenyl)-4-( 1,3be nzodioxol-5-yl)- 1 -(N-methyl-Nprop ylam inocarbo nyl methyl)- pyrrol id in e-3 carboxylic acid: 207 trans, trans-2-(4-Methoxyphenyl)-4-(1 13- 00 benzodioxole-5-yl)-1 -(N-methyl-Nbutylaminocarbonyl)-pyrrolidile-3-carboxyliC acid; 208 trans, trans -2 Met ho xyphefnlyl)-4- (1 ,3- 00 benzodioxol-5-yl)-1-(N-methyl-N-(4methoxyphenyl)aminocarboflyl)-3-pyrrolidifle-3carboxylic acid; 209 trans, trans-2.(4-Methoxyphefl)-4-(1,3- 1 ethyl- Nphenylaminocarbonyl)-pyrrolidile-3-carboxylic acid; 210 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol 1 ethyl- NallylIa mln ocarbon ylm ethyl) -p yr roll dine -3carboxylic acid; 211 trans, trans-2-(4-Methoxyphenyl)- 4 1,3benzodioxol-5-yl)-l1-(N-methyl-N-(nbutyt)aminocarboflylmethyl)-pyrrolidine- 3 carboxylic acid; 212 trans, trans-2-(4-Methoxypheflyl)-4-( 1,3benzodioxol 1 -m ethyl-N isobutylaminocarbonylmethyl)-pyrrolidi ne-3carboxylic acid; 213 trans, trans-2-(4-Methoxyphenyl)- 4 1 ethyl- Ncyclopentylaminocarboflmethyl)-pyrrolidine- 3 carboxylic acid; 214 trans, trans -2 Metho xyPhe nYl)-4-( 1,3- -(N-methyl-N-(2met ho xye thyI) am ino carbon yl -py rro lidin e -3carboxylic acid; WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -182- 215 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-methyl-Nci butoxyethylaminocarbonyl)-pyrrolidifle-3carboxylic acid; 00 216 trans, trans-2-( 1,3- Ben zod ioxol-5-yl) methoxyphenyl)- 1-(N -m ethyl- Npropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 00 217 trans, trans-2-(4-Methoxyphelyl)-4-(1 ,4benzodioxan-6-yl)-1-(N-methyl-Npropylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; 218 trans, trans-2-(4-Methoxypheflyl)- 4 ,3be nzodioxol 1 -m ethyl- Nisopropylaminocarbo nylmethyl)-pyrrolidine-3carboxylic acid; 219 trans, trans-2-(4-Methoxyphenyl)-4-(l ,3- 1 -(N-methyl-Nethyl amin ocarboflyl methyl)-pyrro idifle 3 carboxylic acid; 220 trans, trans-2-(4-Methoxypheflyl)-4-( 1,3benzod ioxol-5-yl)- 1 -(N-methyl-N-( 1m ethyl propyl) am inoca rbonylmethyl)pyrrol id ife- 3 carboxylic acid; 221 trans, trans -2 Metho xyphenY) 4 ben zodioxol 1 -m ethyl- Nphenylam inocarboflyl m ethyl) -pyrrolidi ne-3carboxylic acid; 222 trans, trans-2-(4-Methoxyphenyl)-4-(l .3benzodioxol-5-yl)-l1-(1 -(N-methyl-Np ropyl am inocarbonyl) ethyl) -pyrroli difle- 3 carboxylic acid; 223 trans, trans-2-(4.Methoxypheflyl)- 4 1 (N -methyl -N pro p yIamino carbon yl) ben zyI) -p yr rolid in e-3carboxylic acid; WO 99/06397 WO 9906397PCT/US98/1 5479 00 -183- 224 trans, trans Met hoxypheflyl)-4-( 1,3benzodioxol-5-yi)-1 -(N-ethyl-N- Clpropyl amminoca rbo nyl methyl)- pyrrol idi ne-3carboxylic acid; 00 225 trans, trans-2-(4-Methoxyphelyl)-4-(1 ,3benzodioxole-5-yl)-1 N-ethyl-Nbutylaminocarbonyl)-pyrroidile-3-carboxylic acid; 226 trans, trans-2-(4-Methoxypheflyl)-4-(1,3- 00 benzodioxol-5-yl)-1 -(N-ethyl-N-(4methoxyphenyl)aminocarboflyl)-3-pyrrolidifle-3carboxylic acid; 227 trans, trans-2-(4-Methoxypheflyl)-4-(l ,3- 1-(N-ethyl-Nphenylaminocarbolyl)-pyrrolidile-3-carboxylic acid; 228 trans, trans-2-(4-Methoxypheflyl)- 4 3 benzodi oxol-5-yl)- 1 -ethyl-N allylaminocarbonylmethyl)-pyrrolidile- 3 carboxylic acid; 229 trans, trans-2-(4- Met hoxypheflyl)- 4 .3benzodioxol-5-yI)-1 -(N-ethyl-Nisobutylaminocarboflylmethyl)-pyrrolidifle- 3 carboxylic acid; 230 trans, trans-2-(4-Methoxypheflyl)-4-(1 ,3benzodioxol-5-yt)-1 -(N-ethyl-Ncycl opentyl ami noca rb ofyl methyl) pyrrol id ine- 3 carboxylic acid; 231 trans, trans-2-(4-Methoxypheflyl)-4-( 1,3benzodioxol-5-yi)-1I -(N-ethyl-Nmethoxyethylamilocarboflyl)-pyrrolidifle- 3 carboxylic acid; 232 trans, trans-2-(4-Methoxypheflyl)-4-(l ,3- -(N-ethyl-Nbutoxyethylamiloca rbonyl)-pyrrolidine-3carboxylic acid; WO 99/06397 WO 9906397PCT/US98/15479 00 -184- 233 trans, trans-2-(1I,3- Ben zodioxol-5-yI)-4-(4methoxyphenyl)-1I-(N-ethyl-Np ropyl am inocarbonyl methyl)- pyrrol id ine-3carboxylic acid; 234 trans, trans Met ho xyp henyl) (1,4- 00 benzodioxan-6-yi)-1 -(N-ethyl-Npropyl am inocarbonyl methyl) -pyrrol idi ne-3 carboxylic acid; 00 235 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3benzodioxol-5-yl)-1 -(N-ethyl-Nisopropylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 236 trans, trans-2-(4-Methoxyphenyl)-4-(1,3benzodioxol-5-yt)-1 diethylaminocarbonylmethyl)-pyrrolidifle-3carboxylic acid; 237 trans, trans-2-(4-Methoxyphenyl)-4-( 1 3benzodioxol-5-yI)-1 -(N-ethyl-N-( 1mnethyl pro pyl) am inoca rbonylmethyl)- pyrro i difle-3carboxylic acid; 238 trans, trans ethoxyphenyl)-4- (1,3benzodioxol-5-yi)-1 -(N-ethyl-Nphenylaminocarbonylmethyl)-pyrrolidine-3carboxylic acid; 239 trans, trans etho xyphe nyl)-4-( 1,3- 1 -(N-ethyl-Np ropyl am inocarbonyl) ethyl) -pyrrol idifle-3 carboxylic acid; 240 trans, trans Met hoxypheflyl)-4-( 1,3benzodioxol-5-yl)-1 -(c-(N-ethyl-Npropylaminocarbonyl)benzyl)-pyrrolidifle-3carboxylic acid; 241 trans, trans Methoxypheflyl)-4-(1,3 benzodioxol-5-yl)-l1-(N-methyl-Nisobutylam ino carbonyl methyl)- pyrrolidi ne-3carboxylic acid; WO 99/06397 WO 9906397PCT/US9815479 00 -185- 242 trans, trans -2-(4-Methoxyp henlyl) 4 -l 33- 1 -(N-methyl-Ncyclohexylaminocarboflylmethyl)-pyrrolidifle- 3 carboxylic acid; 00 243 trans, trans-2-(4-MethoxyphefYl) 4 benzodioxol-5-yI)-1

N-

dip ropyl ami nocarboflyl methyl)-pyrrolidifle 3 (Ni carboxylic acid; 00 0 244 trans, trans-2-(4-Methoxypheflyl) 4 (l,3- 0 ~benzodioxol5y)- -(isobutyIoxyethy4pyrrolidine-3-carboxylic acid; 245 trans, trans-2-(4-Methoxypheflyl)- 4 -(l1,3- .(butylsutfonyl)-pyrrolidifle-3carboxylic acid; 246 trans, trans-2-(4-MethoxyphefylY) 4 -(l3- 1- (isopropylsulfolylamifloethyl)-pyrrolidine- 3 carboxylic acid; 247 trans, trans-2-(4-Methoxyp he nyI)- 4 ,3- (eth oxymethyl carbonl lm ethyl) -pyrroidi ne- 3 carboxylic acid; 248 trans, trans-2-(4-Meth0xyphelY) 4 ben zodioxol 1 (2-ethylbutyryl methyl)pyrrolidine-3-carboxylic acid; 249 trans, trans -2-(4-MethoxyphelY) 4 -(N-rnethyl-N-(3,4di methoxybelzyl)amiloca rbo nylm ethyl) py rroli dine- 3-carboxyl ic acid; 250 trans, trans -2 -M ethoxyp heylY- 4 R)-1.(N-methyl-Nprop'ylarninocarbolyl)butyltkpyrrolidine- 3 carboxylic acid; 251 trans, trans-2-(4-Methoxypheny) 4 (l ,3- (1 S)-1 -(N-methyl-Npropylaminocarboflyl)butylk-pyrrolidine- 3 carboxylic acid; 7 WO 99/06397 PCT/US98/1 5479 00 -186- Ct 252 trans, trans-2-(4-M ethoxyphenyl)-4-( 1,3benzodioxol.-5-yl)-1 -(3-isopropoxypropyl)c-I pyrrolidine-3-carboxylic acid; 253 'trans, trans Metho xyp he nyl) (1,3- 00 ben zodioxolI-5-yI)- 1 (5-m ethyl he xyl) -pyrrol idi ne- 3-carboxylic acid; 254 trans, trans-2-(4-Methoxyphenyl)-4-( 1,3c-i benzodioxol-5-yl)-1I-(5-mfethyl-2-hexeflyl)- 0 0 255 trans, trans-2-(4-Methoxypheflyl)-4-( 1r3- 1 -(5-methyl-4-hexenyl)pyrrolidine-3-carboxylic acid; 256 trans, trans-2.(4-Methoxypheflyl)-4-(1,3benzodioxol-5-yl)-l1-(3,5-dimethyl-2-hexeflyl)pyrrolidine-3-carboxylic acid; 257 trans, trans etho xypheflyl) (1,3benzodioxol-5-yl)-1 -(2-(N-methyl-Niso b utyrylIm ina) ethyl) -p yr rolid in e-3-ca rbox y i c acid; 258 trans, trans-2-(4-MethoxyphelY) 4 1,3- 1 -(N-methyl-N-(2 ,2di methylpropyl) aminoca rbo nyl methyl)-pyrroli dine- 3-carboxylic acid; 259 trans, trans-2-(4-Methoxyphefl)-4-(1 ,3benzodioxol-5-yi)-1 -(N-ethyl-Nbutyl am iflocarboflyl methyl) pyrrol idifnle-3 carboxylic acid; 260 trans, trans Met ho xyp helYl)-4-( 1,3benzodioxOl-5-yl)-1 -(N-rnethyl-Nbenzyl amin ocarboflylm ethyl) pyrrol idifle- 3 carboxylic acid; 262 trans, trans-2-(4-Methoxyphefyl)4(5-ifdafyl)-1 (N-m ethyl- N-propyl amilocarboflmethyl) pyrrolidine-3-carboxylic acid; WO 99/06397 WO 9906397PCTIUS98I1 5479 00 -187- 262 trans, trans-2-(4-Methoxyphelyl) 4 2 3 dihyd robe nzofurafl-5-Yl)- 1 -(N-methyl-Nl propyl am inocarbon yl met hyl) -pyrrolidi ne- 3 carboxylic acid; 00 263 trans, trans-2-(4-MethoxypheflY) 4 methylindol-5-yI)-1-(N-methyl-N propylaminocarbonylmethyl)-pyrrolidile- 3 carboxylic acid; 00 0 ~264 trans, trans-2-(4-Methoxypheny)4(2-naphthyI)- 0 (N-rmethyl-N-p ropyl am ifoca rbofllmothyl)' pyrrolidine-3-carboxylic acid;, 265 trans, trans-2-(4-Methoxypheflyl) 4 dimethoxy-4-phenYl) I -(N-methyl-NpropylaminocarboflylmethYl)-PYrroli dine-3carboxylic acid; 266 trans, trans-2-(4-Methoxyphenyl)4(1methoxy- 3 phenyl)-l1-(N-methyl-Npropyl aminocarbofl m ethyl)pyrroli di ne- 3 carboxylic acid; Examples 267-288 Following the procedures described in Example 1 and Scheme 11, the following compounds can be prepared.

267 trans, trans-3(4-Metho xyphe nYl) 5-(l,3- -(propylaminOcarboflylmethyl)piperidine-4-carboxylic acid; 268 trans, trans-3-(4-Methoxyphenyl)5(l13- 1 (aminocarboflylmethyl)piperidine-4-carboxylic acid; 269 trans, trans-3-(4-Methoxyphenyl)5-(l ,3- -(4-fluorobeflzyl)piperidine- 4-carboxylic acid; 270 trans, trans-3-(4-Methoxyphenyl)S5(l ,3benzodioxol 5

-YI)

1 -(2-ethoxyethyl)-piperidifle- 4 carboxylic acid; WO 99/06397 WO 9906397PCTIUS98/15479 00 -188- 271 trans, trans-3-(4-M ethoxyphenyl)-5-( 1,3- 1 -(2-propoxyethyl)-piperidifle- 4-carboxylic acid; 272 trans, trans-3-(4-Methoxyphenyl)-5-( 1,3- 00 ben zodioxolI-5-yI) -I [2-(2-metho xyeth oxy) ethyl]-.

pipe rldine-4-carboxylic acid; 273 trans, trans-3-(4-Methoxyphefl)-5-( 1,3benzodioxol-5-yI)-1 -py ridyl) ethyl] 00 0 piperidine-4-carboxylic acid; 0 ~274 trans, trans-3-(4-MethoxyphelY)5-(1 1 -(inorpholin-4-ylcarboflyl)piperidine-4-carboxyliC acid; 275 trans, trans et hoxyphefnl)S benzodioxole-5-yi)-l1-(butylaminocarboflyl)piperidine-4-carboxylic acid;, 276 trans, trans-3-(4-Methoxypheyl) (l, 3 benzodioxoI-5-yI)-1 methoxypheflylainocarboflyl)3piperidine- 4 carboxylic acid; 277 trans, trans Met hoxypheflY) 5 (l 3- -acetylpiperidine-3-carboxylic acid; 278 trans, trans Met ho xypheflY) 5(1,3 1 -(2-furoyl)-piperidifle-3carboxylic acid; 279 trans, trans-3-(4-Methoxyphefly)-S(l, 3 -(phenylaminocarboflyl)piperidine-4-carboxylic acid; 280 trans, trans-3-(4-MethoxyPhelYl)5-(1,3- I -(allylaminocarbolyrlmethyl)piperidine4-carbOXYlic acid; 281 trans, trans-3- Methoxyp henflY) 5-(l 3- 1-(nbutylaminocarboflylmethy)piperidine 4 carboxylic acid; WO 99/06397 PCTIUS98/15479 00 -189- 282 trans, trans-3-(4-Methoxyphenyl)-5-(l .3benzodioxol-5-yi)-1 -(N-l-butyl-Nmethylaminocarbonylmethyl)-piperidifle- 4 carboxytic acid; 283 trans, trans-3-(4-Methoxypheflyl)5(l,3- 00 benzodioxol.5-y)-1-(pyrrolidifl1ylca rbonylm ethyl)-pipe ridile-4-carboxylic acid; 0 284 trans, trans-3-(4-Methoxyphenyl)-5-(l 3- 00 benzodioxol-5-yi)-1 (isobutylaminocarbonyl methyl) -piperid~ne- 4 carboxylic acid; 285 trans, trans-3-(4-Methoxyphel) .3- 1- (cyclopentylamilocarboflmethyl)-pi peridine-4carboxylic acid; 286 trans, trans-3-(4-Methoxyphenyl)5(l .3- 1 -(morpholin-4ylaminocarbonylmethyl)-piperidifle-4carboxylic acid; 287 trans, trans-3-(4-MethoxypheflYl)5(l 3- -(2-phenoxyethyl)-PiPeridifle- 4-carboxylic acid; 288 trans, trans-3-(4-MethoxyphenYY) 1 (methoxyethylamilocarboflYl)piperidine-4-carboxylic acid.

trans. trans- 2(4-Methoxyphefll)'4(l.3-benzodioxol-5-yl)-l (4dibutylaminophefl)yflrrolidife3carboxylic acid 4-Nitro-iluorobeflzefe, ethyl trans, trans-2-(4-methoxypheflyl)- 4 (1 3-be nzodi oxol.5-yl) -pyrrolid ife-3-carboxyl ate (example 6A) and diisopropyl ethylamine are heated in dioxane to give ethyl trans,trans-2- (4-methoxypheflyl)-4-(i ,3-benzodioxol-5-yl)- 1 -(4-nitrophenyl)pyrrolidine-3-carboxyl ate. The nitro compound is hydrogenated to the 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-

WO 99/06397 WO 9906397PCT/U598/I 5479 00 -190dibutylaminophenyl compound, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.

Exmpe 9 00 trans trans-2-(4-MethoxyphenYl)- 4 .3-benzodioxol-5-yl)-1 dibutylamino-1yrimidne4-yl)-SDyrrolidile-3-carboxylic acid 2-(Dibutylamino) 4-chioropyrimidine is prepared from 2-4- Ni dichloropyrimidine according to the method of Gershon Heterocyclic 00 S Chem. 24, 205, 1987). This compound, ethyl trans, trans-2-(4methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolj din e-3carboxyl ate (example 6A), and di-isopropyl ethylamine are heated in dioxane to give the intermediate ethyl ester, which is hydrolyzed with sodium hydroxide using the method of example 1 D to give the title compound.

trans. trans-2-(4-MethoxyhenYl-4- 1 .3-benzodioxol-5-Vl)- 1 -(N-butyl-Np2henylaminocrboflylmethyfl)-yrrolidifle-acarboxylic acid The title compound was prepared according to the general procedure of Example 1. IH NMR (CD 3 OD) 8 0.87 1.2-1.35 1.35-1.5 2.78 (in, 3.10 3.26 (d,1H,J=15); 3.44 (dd,1H,J=5,10); 3.5-3.7 3.77 (m,11H); 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 31

H

34

N

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

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

Examole 292 Sodiurn trans, trans-2-(4- Methoxypheflyfl-4-( 1. 3-benzodioxol-5-yl)- 1 N-di(nbut vI)aminocarbpfl Vimeth v/)-Drroli dinle- 3-carboxyate Example 292A Ethyl 3(4methoxyohnyl-3-oxO o- oate 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 nllnwed to settle. 20 L of the toluene solution was aspirated. 28 L of WO 99/06397 PCTIUS98/1 5479 00 -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 00 added over 20 minutes. When additions were complete, the jacket Stemperaturewas reduced to 100 C and stirring continued for 16 hours.

O A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized 0o water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% aqueous sodium chloride The organic solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.

Examole 292B 3.4-Methvlenedioxv- 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 set to C and the reaction solution cooled to a temperature of +3.50 C. A 210 C solution of 3.10 kg (38.8 moles) 50% aquous sodium 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 26° 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 WO 99/06397 PCT/US98/15479 00 -192dichloromethane. The combined organics were dried over 1.32 kg C magnesium sulfate and filtered through Whatman #1 paper. The volume c was reduced to 20% and the solution cooled to 40 C. Filtration through Whatman #1 paper, followed by ambient temperature drying in vacuo with an air leak afforded 1.584 kg of a first crop Concentration Sof 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.

00 0 Example 292C Ethyl 2-(4-methoxybenzoylv-3-(1.3-benzodioxol-5-yl)-4-nitrobutanoate Into a 45-L stirred reactor at ambient temperature were charged 5.819 kg (30.1 moles) 3,4-methylenedioxy-1-(2-nitroethenyl)-benzene and 24 L ethyl acetate A solution of 5.355 kg (24.1 moles) ethyl 3-(4methoxyphenyl)-3-oxopropionate in 16 L ethyl acetate was added. 280 g (275 ml, 1.84 moles) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene in four equal portions was added over a 2.5 hour period. The reaction mixture was filtered through dicalite and the resulting filtered solution was used in the next step without any further purification.

Example 292D Ethyl 2-(4-methoxvDhenyl-4-(1.3-benzodioxol-5-y)l-4.5-dihydro-3Hpyrrol -3-carboxvlate 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 00 C and filtered. The solid was washed with 2 L of 85:15, hexane: ethyl acetate (00 The solids were dried in vacuo at 500 C to a constant weight of 193.4 g (21% yield, melting point 80-81° C) of the WO 99/06397 PCT/US98/15479 00 -193- M title compound. A further 200 g (23% yield) of product was obtained from the mother liquors.

Example 292E 0 Ethyl 2-(4-methoxvphenvl)-4-(1.3-benzodioxol-5-vl-nvyrrolidine 3carboxylate Into a 12-L flask equipped with magnetic stirring, addition funnel, N temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4- 0 o methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro- 3 H iO 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 1 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 2 g of the title compound as a thick yellow oil.

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

The reaction vessel was degassed with nitrogen. 13.2 L ofacetonitrile, 3.66 L diisopropylethylamine (2.71 kg, 20.9 mol), and 1.567 kg dibutylamidomethyl bromide (6.26 mol) were added. The mixture was refluxed at 780 C for 17 hrs. After the disappearance of starting material the mixture was concentrated until crystals formed. The solid was filtered and washed with 4 L ethyl acetate (00 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 MgS04 and filtered.

WO 99/06397 PCT/US98/15479 00 S-194- C Concentration as above provided 3.112 kg (96 yield) of the title c compound as a dark oil.

Example 292G trans. trans-2-(4-Methoxyvhenvl-4-(1.3-benzodioxol-5-vl)-Dvrrolidine 3-carboxvlate and preoaration of trans.trans 2-(4-methoxvohenvyl-4- O (3.4-dioxvyhenyl-ovyrrolidine-3-carboxylic acid ethyl ester oo Into a 35-L reactor equipped with overhead stirring, nitrogen inlet, and condenser was charged 3.112 kg ethyl 2-(4-methoxyphenyl)- 1 4-(3,4-methylenedioxyphenyl)-pyrrolidine 3-carboxylate (5.78 mol).

16.4 L of absolute ethanol was added and the reaction vessel was degassed with nitrogen. 0.115 kg of sodium ethoxide (1.69 mol) was added and the mixture was refluxed at 79° C for 1 hr. The mixture was cooled to 15° C and 5 L of 7.6 M NaOH solution (38.1 mol) was added. The 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 50° 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-methoxvyhenvl-4-( 1.3-benzodioxol-5-yl- 1 (N.N-di(n-butylaminocarbonylmethylv ovrrolidine 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-carboxyiic acia (0.927 ky, I-osI n-ou). A souti.on c WO 99/06397 WO 9906397PCT/US98/15479 00 -195- S0.0720 kg NaOH (1 .80 mat) dissolved in 4.65 L methanol was added. The reaction mixture was concentrated to an oil. Pentane (4 L) was added and the solution concentrated again. Pentane (4 L) was added again and concentration of this solution gave a light tan foam. The foam was dried in vacua at 500 C to a constant weight of 0.937 kg (97% yield) of the 00 title compound.

00 trans- trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodi oxol-5-yfl)-1 fdecahydroisoquinolin-2- carbonylmethyll-oyrr~lidine-3-carboxylic The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) shows a mixture of isomers. MS

(DCI/NH

3 m/z 521. Anal calcd for C 30

H

36

N

2 0 6 1.3 TEA: C, 58.54; H, 6.62; N, 4.19 Found: C, 58.34; H, 5.58; N, 4.00 Example 294 trans -trpns-2-(4- Methoxy h enyfl-4-(1 ben zodi oxoI- 5-yfl-1 4r3,3dimethylpiperidinyl- carbonylmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (C0 3 0D, 300 MHz) indicates presence of rotamers. 8 0.84 3H), 0.86 3H), 1.35-1.6 (in, 4H), 3.83 3H), 5.96 2H), 6.81 1H, 6.90 (dd, 1H, 7.01 2H, 7.03 1H), 7.47 2H, MS (DCI/NH 3 m/z 495. Anal calcd for C 2 8H 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 trans- trans-2 Meth oxyp he nyl)-4-( 1.3-ben zodi oxol- 5-yi) 1 4r2-(Wpropyl-N isobutoxycarbonyl amino) ethyfl-12yrro lid ine-3-carbo xyl ic acid The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and isobutyl chloroformate for isobutyryl chloride in Example 61C.

The crude product was purified by trituration with 1:1 diethyl ether/ hexane. The resulting solid was dissolved in CH 3 CN and water and lyophilized to give the product as a white solid. 1 H NMR (CDC1 3 300 MHz) 8 0.80 3H-, 0.92 (in, 3H), 1.43 2H, J=7Hz), 1.7-1.9 (in, 1IH), 2.72 (in, 1H), 2.90 (in, 2H), 3.10 (in, 2H), 3.25 (in, 2H), 3.40 (in, 1H), WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -196- S3.55 (in, I 3.62 (in, 1 3.7-3.9 (mn, 2H-) 3.78 3H), 5.95 2H), 6.72 I1H, J= 8Hz), 6.82 (in, 3H), 7.00 1H), 7.30 2H, J=8Hz). MS (DCI/NH3) mWe 527 Anal calcd for C 29

H

38

N

2 O6 -0.5 H 2 0: C, 65.03; H, 7.34; N, 5.23. Found: C, 65.13; H, 6.96; N, 4.95.

00 -trans- Met hoxylh e nyfl-4-(1 ben zod ioxol-S-yl- 141ri.2.3.4: NI tetrahydroisoguinolifl-2- carbonylmethyll-Dvrrolidile-3-carboxylic 00 The title compound was prepared using the.procedures described in example 1. NMR (CD3OD, 300 MHz) indicates presence of rotamers. 8 2.97 (mn, 4.68 3H), 5.97 2H), 6.83 1 H, 6.9-7.0 (in, 3H), 7.03 1IH,- 7.1-7.3 (in, 4H), 7.4-7.5 (in, 2H). MS (DCI/NH3) m/z 515.

trans- trans-2 Methoxyp he nlb-4-(1I.3-ben zod ioxol -5-yfl- 1 4r2-(Wpropyl- N-dim ethyl ami nocarboflyl ami no~ethyl1oyrroli din e-3-ca rbo xyliCQ The title compound was prepared by the methods detailed in Example 61, but substituting propylamine for methylamine in Example 61B and dim ethyl carbamyl chloride for isobutyryl chloride in Example 610. The crude product was purified by preparative HPLC (Vydac jiCiB) eluting with a 10-70%/ gradient of CH 3 CN in 0.1% TFA. The desired fractions were lyophilized to give the product as a white solid. 1 NMR (CDCI3, 300 MHz) 6 0.70 3H-, J=7),,1.28 (in, 2H), 2.75 3H), 2.82 (mn, 2H), 3.1-3.45 (in, 4H), 3.70 (in, 1 3.80 3H), 3.90 (in, 3H), 4.72 (in, 1 5.95 2H), 6.75 I1H, J= 8Hz), 6.87 (in, 7.05 1 7.40 (d, 2H, J=8Hz). MS (DCI/NH 3 Wle 498 Anal calcd for C 27

H

35

N

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

Example 298 trans. trans- 2 -(4-Meth oxyph eflyfl- 4 (l.3-benzodi oxol -5-yb- 1 carboxylic acid Using the procedures described in Eample 66, the title compound mrannrrard n+ vpllow solid. m.rD. 85-870C. 1 H NMR (CDC13, 300 MHz) WO 99/06397 WO 9906397PCT/US98/I 5479 -197- 8 0.77 J=7.5Hz, 3H), 1.38 (sextet, J=7.5Hz, 2H), 2.20-2.29 (in, 11-), 2.57-2.66 (in, 11H), 2.82-3.15 (in, 4H), 3.22 J=7.5Hz, 2H) 3.38 (dd, __J=3Hz,J=9Hz, 1 3.49-3.57 (in, 1 3.59 J=9Hz, 1 3.83 3H), 5.96 2H), 6.73 J=8Hz, 1H), 6.82 (dd, J=lHz,J=8Hz, 1H), 6.87 (d, 00 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 CI Example 299 00 0trans. trans-2-(4-Methoxyphel)f-4-( 1.3-benzodioxol-5-yl)-1 0 2oy---etnsloygioehl-yrlcie3croyi 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 (CDC1 3 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, 1H), 2.70-3.08 (in, 7H), 3.15-3.32 3.42 (dd, J=3Hz,J=9Hz, 1H), 3.52-3.57 (in, 3.63 J=9Hz, 11H), 3.80 3H), 5.95 2H), 6.73 J=7.5Hz, 1H), 6.83 (dd, J=lHz,J=7.5Hz, 1H), 6.87(d, J=8Hz, 2H), 7.00 J=lHz, 1H), 7.32 J=BHz, 2H). MS (DCI/NH3) Wne 561 Example 300 trans. trans-2-(4-Methoxylhenyl)-4-( 1.3-benzodioxol-5-yfl- 1 prly--4tilooehxbeznsloy~mn~ty) pyrrolidine-3-carbgxylic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.122-124 0 0. 1 H NMVR (CD3OD, 300MHz) 80.75 J=7.5Hz, 3H), 1.26-1.45 (in, 2H), 2.96-3.08 (mn, 2H), 3.23 (bs, 2H), 3.35-3.45 (in, 2H), 3.52 J=lOHz, 1H), 3.81 J=9Hz, 2H), 3.86 (s, 3H), 3.92 J=9Hz, 1H), 4.63 J=lOHz, 1H), 5.97 2H), 6.82 (d, J=9Hz, 1H), 6.93 (dd, J=3Hz,J=9Hz, 1H), 7.06-7.08 (in, 3H), 7.46 (d, J=9Hz, 2H), 7.56 J=9Hz, 2H), 7.89 J=9Hz, 2H). MS (DCI/NH3), i/ 651 (M+H) 4 WO 99/06397 PCT/US98/15479 00 -198trans. trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl-1 p ropyl- N-(2-m ethyl -2-propenesulf onyfl)ami no)e thyl)-pyrro lid ine-3- Using the procedures described in Example 66, the title compound 00 was prepared as a white solid. m.p. 69-711oC.. 1 H NMR (CDCI3, 300MHz) 8 0.79 J=7.5Hz, 3H), 1.93 (sextet, J+7.5Hz, 2H), 1.92 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- 00 3.68 (in, 2H), 3.66 J=9Hz, I1H), 3.80 3H), 4.92 1 5.07 I1H), 5.97 2H), 6.74 J=7Hz, 1H), 6.82-6.89 7.01 7.33 (d, J=9Hz, 2H). MIS (DCI/NH3), W/e 545 trans -trans-2-(4- Methoxylhenl)-4-(1 .3-benzodioxoI 14-2ethyl pi oeridi nyl-carbonyl methyl]-yrrol idile-3-carboxyl ic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD 3 OD, 300 MHz) shows a mixture of isomers. 8 0.75 3H, 1.4-1.7 (mn, 8H), 3.84 3H), 5.96 2H), 6.83 1 H, 6.91 1H, 7.0-7.1 (in, 3H), 7.52 2H, MS (DCI/NH 3 mlz 495. Anal calcd for C 28

H

34

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 trans. trans-2-(4-Methoxyp~henyl)-4-( 1.3-benZodioxol-5-yl)- 1 propyl-N-(2-methylproganesulfonyl)amino~ethylDyrroldine- 3 Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p. 72-730C. 1H NMR (CDC13, 300 MHz) a 0.82 J=7.5Hz, 3H),1.04 J=6Hz, 6H), 1.44(q, J=7.5Hz, 2H), 2.15-2.33 2.57-2.75 (in, 2H), 2.84-3.08'(mn, 3H), 3.12-3.21 (mn, 1H), 3.23- 3.45 (in, 1H), 3.43 J=llHz, 1H), 3.55-3.62 (in, 1H), 3.66 J=9Hz, 1H), 3.80 3H), 5.95 2H), 6.75 J=9Hz, 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 WO 99/06397 WO 9906397PCT/US9815479 -199- Example 304 trans, trans-2-(4-Methoxyphenyfl-4-(l .3-benzodioxol-5-yfl)-1 propyl-N-heptanesulfonylamiolethyl-pyrrolidifle-3-carboxylic acid Using the procedures described in Example 66, the title compound 00 was prepared as a white solid. m.p.58-59 0 C. 1H NMR (CDC13, 300MHz) 8 0.80(t, J=7.5Hz, 3H), 0.88 J=7Hz, 3H), 1.23-1.36 (in, 8H), 1.94 (q, 5J=7.5Hz, 2H), 1.71(quintet, J=7Hz, 2H), 2.23-2.32 (in, 1H), 2.70-3.09(m, 7H), 3.13-3.32 3.43(dd, J=3Hz,J=9Hz, 1H), 3.52-3.58(m,1H), 00 0 3.65(d, J=9Hz, 1H), 3.80 3H), 5.96(s, 2H), 6.73 J=7Hz, 1H), 6.83 Ni (dd, 1=1Hz, J=7Hz, 1H), 6.87(d, J=9Hz, 2H), 7.O1(dr J=lHz, 1H), 7.32(d, J=9Hz, 2H). MS (DCI/NH3) mWe 589 M+sH)+.

Examl 0 trans- trans-2-(4-Meth oxypheflyfl-4-( 1.3-ben zodi oxol- 5-yfl 1 -f 2-(Nethyl-N-ethoxycarbonylamino~ethyl-pyrrolidine-3-carboxylic acid Prepared by the methods detailed in Example 61, but substituting ethylamine for methylamine in Example 61B and ethyl chloroformate for isobutyryl chloride in Example 61 C. The crude product was purified by preparative HPLC (Vydac jiCiB) eluting with a 10-70% gradient of CH 3

CN

in 0.1% TEA. The desired fractions were lyophilized to give the product as a white solid. 1 H NMR (CDCI3, 300 MHz) 8 0.90 3H, 1.22 (in, 3H), 3.0-3.2 (in, 4H), 3.42 (in, 2H), 3.78 3H), 3.82 (in, 4H), 4.10 2H, J=7Hz), 3.5 (br s, 1 5.97 (dd, 2H, J=1,7HZ), 6.72 1 H, J= 8Hz), 6.84 (mn, 3H), 7.00 1H), 7.42 2H, J=8Hz). MS (DCI/NH3) mWe 485 (M+H) 4 Anal calcd for C 26

H

3 2N207 -1.2 TFA: C, 54.90: H, 5.39; N, 4.51. Found: C, 55.01; H, 5.36; N, 4.56.

trans. trans-2-(4-Methoxylhenyl)-4-(1 .3-benzodioxol-5-yfl- 1 propyl.N-hexanesulfonylainino~ethyfl)-Drrolidine-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 (CDC13, 300MHz) 8 0.80(t, J=7.5Hz,3H), 0.89(t, J=7Hz, 3H), 1.25-1.36(m, 6H), 1.53(sextet, 2H), 1.72(quintet, J=7Hz, 2H), 2.23-2.32(m, 1H), 2.72-3.08(mn, 7H), 3.15-3.32(mn, 2H), 3.43(d, J=9Hz, 1H), 3.55-3.62(m, 1H), 3.65 (d, J=lOHz, 1H), 3.80(s, 3H), 5.96(s, 2H), 6.74(d, J=7.5Hz,1H), 6.82(d, WO 99/06397 WO 9906397PCT/US98/1 5479 00 -200- J=7.5Hz,1H), 6.87(d, J=9Hz, 2H), 7.O1(s,1H), 7.32(d, J=9Hz,2H). MS (DCI/NH3), m/e 575 Examgle 307 00 trans -trans-2 Ethylphenyfl-4-(11.3- ben zodioxol-5-yi)-1I -rN. N-di(nbutyl)aminocarbonylmethyll-pyrrolidifle-3-carboxylic acid.

The title compound was prepared using the procedures described 0 0 (prepared by the method of Krapcho et al., Org. Syn. 47, 20 (1967) 0 starting with 4'-ethylacetophenone) in procedure 49B. NMR (C~DC 3 300 MHz) 8 7.31 (2H, d, J=8Hz), 7.16 (2H1, d, J=BHz), 7.03 (1 H, d, J=3Hz). 6.86 (1 H, dd, J=8&3Hz), 6.73 (1 H, d, J=9Hz), 5.94 (1H. d, J=4Hz), 5.92 (1 H, d, J=4Hz), 3.77 (1 H, d, J=9Hz), 3.60 (1H, in), 3.53-3.23 (5H, in), 3.13-2.90 (4H, in), 2.73 (1H, d, J=l4Hz), 2.62 (2H, q, J=9Hz), 1.45 (2H, in), 1.40- 1.10 (6H, in), 1.02 (2H, in), 0.87 (3H, t, J=7Hz), 0.78 (3H, t, J=7Hz). m/e (DCl, NH 3 509* Anal.calc. for C 30

H

4

ON

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

Found C 70.80, H 7.85, N 5.25 Examgle 308 trans -trans-2-(4-M ethoxyghenyfl-4-( 1.3-ben zodi oxol- 5-yi)- I -r2-(Np2ropyl-N-(2-chloroethoxy~carbonylamino~ethyll-pyrrolidifle-3carboxylic acid Prepared by the methods detailed in Example 61, but substituting propylamine for inethylamine in Example 61 B and 2-chloroethyl 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 lyophilized to give the product as a white solid. 1 H NMR (00013, 300 MHz) 8 0.80 3H, J=7), 1.22 (in, 2.15 (mn, 1 2.75 (in, 1 2.85 (in, 1 3.1 (in, 3.25 (in, 3.5 (mn, 3H), 3.65 (in, 3.80 4.18 (mn, 1 4.30 (in, 1IH), 5.98 2H), 6.72 (mn, 1H), 6.82 (mn, 3H1), 7.00 (in, 1H), 7.30(m, 2H).

MIS (DCI/NH 3 m/e 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, 5.10.

WO 99/06397 WO 9906397PCTIUS98/15479 00 -201- Strans-trans-2-(2-MethoxyethYl 4 -(1.3-benzodioxol-5-yfl-1 -(N.N-di(n- CI butyflaminocarboflylmethYl12yrrolidine3carboxyi~c acid.

The title compound was prepared using the procedures described in 00example 1, substituting ethyl 5-rnethoxy-3-oxoPefltafloate for ethyl 4- C* methoxybenzoylacetate in Example IA. The title compound is a yellow foam. I H SNMR (CDC1 3 300 MHz) 8 0.91 J=7Hz) and 0.95 J=7Hz, 6H total), 1.28-1.41 (br N m, 4H), 1.45-1.63 (br m, 4H), 2.00-2.20 (br m, 3.06 (br t, J=9Hz, 1H), 3.30 (s) 00 and 3.20-3.68 (br m, 11 H total), 3.72-4.10 (br mn, 4H), 5.92 2H), 6.72 S 1H), 6.82 (dd, J=1.5, 8.5Hz, 1H), 6.91 J=1.5Hz, 1H); MS (FAB) mle 463-(M+H)+.

Anal calcd for C 2 sH 3 8N 2 05-H2O: C, 62.48; H, 8.39; N, 5.83. Found: C, 62.13; H, 8.15; N, 5.69.

Example 310 transa. trans- 244- Meth oxyphe nyl 4 (1 be n zod ioxol 1 (N ethyl-N-n-pentanegulfonylamino)ethyl)-DYrrolidine- 3 -carboxYlic acid Using the procedures described in Example 66, the title compound was prepared as a white solid. m.p.57-58 0 C. 1H NMR (CDC13, 300MHz) 8 0.89(t, J=7Hz, 3H), 1 .06(t, J=7.5Hz, 3H), 1.26-1 .37(m, 4H), 1 .72(quintet, 2H), 2.22-2.32(m,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) We 547 Eape3 trn-rn-2(-ehx ~ey)4(.3-benzodioxgl-5-Yl)- 1 -f NNdicycl ohexyl amino carbonylmethyll-pyrrolidifle-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 1 H, 6.86 (dd, 1 H, 6.95 (d, 2H, 7.04 1H, 7.38 2H, MS (DCI/NH3) m/z 563.

Anal calcd for C 33

H

4 2N206 0.5 H 2 0: C, 69.33; H, 7.58; N, 4.90 Found: C, 69.42; H, 7.29; N, 4.78.

WO 99/06397 WO 9906397PCTIUJS98/1 5479 00 -202- Exam 32 trans -trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yfl- I -r2-(Np ropyl-N -te rt-but oxycarbonyl am 4no) ethyll-pyrro Iidi ne-3-carboxylic acUid 00 The title compound was prepared using the procedures described in example 61, substituting propylamine for aqueous methylamine in Example 61 B and di-tert-butyidicarbonate for isobutyryl chloride in N0 Example 61C. NMR (CD3OD, 300 MHz) suggests presence of rotamers 8 S 0.81 3H, 1.2-1.5 (in, 11H-), 3.78 3H), 5.92 (dd, 2H, J=1,2), S6.74 1IH, 6.84 (dd, 1H, 6.92 2H-IJ=9), 6.99 (bd s, 1H), 7.35 2H, MIS (DCI/NH3) m/z 527. Anal calcd for C 29

H

38

N

2 07: C, 66.14; H, 7.27; N, 5.32 Found: C, 66.,05; H, 7.36; N, 5.15.

trans- trans-2(4Methoxy3-fuorophe1yl)- 4 1-[N.N-di(n-butyflaminocaronylmethyl-yrrolidine-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. NMR (CDC13, 300 MHz) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.03-1.50 (in, 8H), 2.82 J=l3Hz, 1H), 2.90-3.13 (in, 4H), 3.20-3.50 (in, 3H), 3.39 J=13H, 1H), 3.55-3.65 (mn, 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 (mn, 2H), 6.99 J=2Hz, 1H), 7.06 (in, 2H).

Anal calcd for C 29

H

37 N206F: C, 65.89; H, 7.06; N, 5.30 Found: C, 65.82; H, 7.13; N, 5.29.

Examogle 314 transa.trans-2-(ProD~yll- 4 .3-benzodioxol-5-yl-l-(2-(N-Drogylpentane su fonlpm ino) ethyl) 1yrroliding- 3-ca rboXyl ic acid Examlle 314A Propyl ~entanesulfonamide Pentane sulfonyl chloride (687 mg, 4.03 mmol) was dissolved in 5 mL

CH

2

CI

2 and added to an ice-cooled solution of n-propylamine (0.40 mL, 4.82 minol) and ethyldiisopropylamine (0.85 mL, 4.88 mmol) in 5 mL CH 2 01 2 under a nitrogen atmosphere. The reaction was stirred at 0 00 for 30 min, then at 25 00 for 4 h. The soiuijurj i w paOi-Gne newc 20K fIANA n Nii NHqrO 4 nnr 25 mL WO 99/06397 WO 9906397PCT/US9815479 00 -203- 0H 2 C12. The organic phase was washed sequentially with 25 mL H 2 0 and 25 mL brine, then dried (Na 2 SO4), filtered, and concentrated in vacua to provide 739 mg NI (3.83 mmol, 95%) of the title compound as a white solid. TLC (25% EtOAc-hexane) RI 0.23; 1 H NMR (CDC13, 300 MHz) 8 0.92 J=7Hz, 3H), 0.97 J=7Hz, 3H), 1.28- 00 1.50 (br m, 4H), 1.52-1.68 (in, 2H), 1.75-1.90 (br m, 2H), 2.98-3.06 (in, 2H), 3.08 (q, J=6Hz, 2H), 4.10-4.23 (br m, 1H); MS (DCI/NH 3 m/e 211 00 Ethyl trans. trans--4-( 1. 3-benzodioxol-5-yfl- 1 -(2-bromoethyl-2-D2rolDy-rrolidine-- The title compound was prepared according the procedure of Example 61A, substituting the compound of Example 94B for the pyrrolidine mixture.

Ethyl trans. trans-2-LPropyl)-44(1. 3-ben zodioxol-5-l)- 1 -(2-(N-oroQYl- 12entanesulfonvlainino~ethyl~Dyrrolid ine-3-carboxylate A solution of the compound of Example 314A (6.6 mng, 34 iimol) in 0.1 mL DMF was treated with sodium hydride (2 mg, 60% oil dispersion, 1.2 mg NaH, jimol). The resulting mixture was stirred at room temperature for 15 min, then a solution of the compound of Example 189B (9.0 ing, 22 gmiol) in 0.1 mL DMF was added, followed b y 0.5 mg of tetra-n-butylanfiuin iodide. The reaction was sealed under argon and stirred at 60 0 C overnight. The reaction was concentrated under high vacuum, and the residue was partitioned between 2 mL of saturated aqueous NaHCO3, 1 mL water and 5 mL EtOAc. The organic phase was washed with 1 mL brine, dried by passing through a plug of Na 2 SO4, and the filtrate concentrated in vacua 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.

Eane34 trans. trans-4- (1 .3benzodioxol-5-lil-2-(ProDyl)-1 -(2-(N-12rogylgentanesulfonylamino~ethvl)1yrrolidine 3 carboxylic acid The title compound was prepared according to the procedure of Example 71C. 1 H NIMR (CDC13, 300 MHz) 8 0.88-1.00 (in, 9H), 1.20-1.55 (br m, 6H), 1.55-1.68 (mn, 3H), 1.70-1.85 (br mn, 2H), 1.90-2.16 (br in, 2H), 2.84-3.26 (br mn, 6H), 3.26-3.90 (br mn, 6H), 5.95 2H), 6.76 J=8Hz, WO 99/06397 WO 9906397PCT/US98/1 5479 -204- 1 1H), 6.79 (in, 1 6.93 (br s, 1 HRMS (FAB) calcd for C 25 1- 41

N

2 0 6

S

497.2685, found 497.2679.

Examle31 00 trans. trans-2-(4-Methoxylhenyl)-4-( 1.3-benzodioxol-5-yfl)- progyl-N-dimethylsulfamoylamino')ethyl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 66, the title compound N was preapred as a white solid. m.p.59-61 0 C. H NMVR (CDCI3, 300MHz) 8 00 0-.79 J=7.5Hz, 3H), 1.45(sextet, J=7.5Hz, 2H), 2.22-2.31(m,1H), 2.65(s, N1 6H), 2.70-2.79(m, IH), 2.85-3.04(m, 4H), 3.09-3.32(m, 2H), 3.40(d, J=9Hz, 1H),3.55 J=9Hz,1H), 3.65(d, J=9Hz,1H), 3.81(s, 3H), 5.96(s,2H), 6.75(d, J=9Hz, 1H), 6.83(d, J=9Hz, 1H), 6.88(d, J=9Hz, 2H), 7.02(s, 1H), 7.34(d, J=9Hz, 2H). MS (DCI/NH3) m/e534 trans -trans-2-(4-Methoxphelyl)-4-(1 .3-benzod ioxol-5-yfl)-1 -r2-(Npropyl-N-r4-methoxyohenyllsulfonylaino'~proDyI-pyrrolidine3- -1 -(3-bromopropyfl Drrolidine-3-carboxylate A 2:1 mixture of trans-trans and cis-trans ethyl 2-(4methoxyphenyl)-4-( 1,3-benzodiox-5-yl) -pyrrolidi ne-3-carboxyl ate (4.00 g; prepared according to example 1C), 32 ml dibromopropane, and 200 mng 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 (Na2SO4) and the solution concentrated. The residue was chromatographed on silica gel eluting with 5:1 hexane:EtOAc. yielding 5.22 of the title compound.

WO 99/06397 WO 9906397PCT/US98/I 5479 00 -205- Exmle36 SEthyl trans-trans and cis-trans 2-(4-MethoxynhenylI-4-(1 .3-benzodioxc-i 5-yi) -14-3-progylaminopropyfl gyrrolidine-3-carboxylate The compound described in Example 316A (5.22 g) was heated at 800 for 2 hrs.with 35 ml. ethanol, 2.5 g. propylamine and 35 mg. sodium 00 Siodide. The solvents were removed in vacuo. The residue was dissolved Sin toluene, shaken with potassium bicarbonate solution and dried S(Na2SO4). The soilution was concentated in vacuum to give 4.96 g of the 00 title compound as an orange oil. This was used in the next step without 0 purification.

trans mtrans-2 et hoxphefl)f- 4 -(1.3-be nzodioxol-5-yfl- 1 -r2-(Npropyl-N-r4-methoxyphenyllsulfonylamino)Propy-1Dyrrolidine- 3 carboyic acid Using the method described in example 66, the compound prepared in Example 316B was reacted with 4-methoxybenzenesulonyl chloride in acetonitrile containing diisop ro pyl ethyl ami ne. The resulting product was chromatographed on silica gel (30% EtOAc in hexane), and hydrolyzed to the title compound by the method of example ID. NMR (CDCI3, 300 MHz) 8 0.83 J=7Hz, 3H), 1.40-1.52 (in, 2H), 1.56-1.70 (in, 2H), 2.00-2.11 (in, 1H), 2.40-2.51 (in, 111), 2.69-2.78 (in, 1H), 2.84-3.03 (in, 4H), 3.19-3.34 (in, 2H), 3.48-3.59 (in, 2H), 3.80 3H), 3.86 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.85 J=BHz, 3H), 6.93 J=BHz, 2H), 7.02 J=2Hz, 1H), 7.29 J=8Hz, 2H), 7.69 J=BHz, 2H). Anal calcd for C 32

H

3 8N 2 08S: C, 62.93; H, 6.27; N, 4.59. Found: C, 62.97; H, 6.39; N, 4.45.

Example317Z trans-trans-2-(4-Methoxpheflyl)V 4 4 l .3-benzodioxol-5-yfl-1 -f2-(N4- 12ropyl.Nmlpropylsulfonylamino)12ropyll12yrrolidine- 3 -carboxylic acid Using the method described in example 66, the propylainino compound prepared in Example 31 6B was reacted with propanesulfonyl chloride in acetonitrile containing diisop ropyl ethyl aiine. The resuling product was chromatographed on silica gel (30% EtOAc in hexane) and hydrolyzed to the title compound by the method of example 1 D. NMR (CDC13, 300 MHz) 8 0.85 J=7Hz, 3H), 1.02 J=7Hz, 3H), 1.47-1.60 WO 99/06397 WO 9906397PCTIUS98/I 5479 00 -206- S(in, 2H), 1.65-1.85 (mn, 4H), 2.04-2.16 (in, 1IH), 2.42-2.57 (in, I1H), 2.72- 3.11 (in, 5H), 3.25-3.41 (mn, 2H), 3.50-3.62 (mn, 2H), 3.80 3H), 5.85 2H), 6.72.(d, J=BHz, 1H), 6.80-6.90 (mn, 3H), 7.02 J=2Hz, 1H), 7.30 (d, J=9Hz, 2H). Anal calcd for C 28

H

38 N207S: C, 61.52; H, 7.01; N, 5.12 00 Found: C, 61.32; H, 7.01; N, 5.01.

Example318 (1 trans, trans--2-(3.Fluoro-4-methoxyflhenyl)P4-(1 00 Using the procedures described in Example 313 and Example 66, the title compound was prepared as a white solid. m.p.66-68 0 C. 1 H NMR (CDC13, 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(mn, 2H), 2.25-2.33(m, 1H), 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(mn, IH), 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=BHz,1 6.92(t, J=8Hz,1H), 6.97(d, J=lHz, 1H), 7.12(d, J=8Hz, 1H), 7.18(dd, J=lHz,J=l2Hz, 1H). MS (DCI/NH3) mle 579 trpns-trans-2-(4-Pyridilyfl-4-(1 .3-benzodioxol-5-yfl-1 -rN.N-di(nbutyflaminocarbonylnethyll-2yrroidile-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 ethoxybenzoyl) acetate. m.p. 131-132 0 C. NMR (CDCI3, 300 MHz) 8 0.82 J+7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.90 (dd, J= 7Hz, 9Hz, 1H), 2.970(d, J=l3Hz, 1H). 3.00-3.25 (in, 4H), 3.32 (in, IH), 3.39 (d, J=l3Hz, IH), 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

3 5N305: C, 67.34; H, 7.33; N, 8.73 Found: C, 67.39: H, 7.45; N, 8.61.

WO 99/06397 WO 9906397PCT/US98/1 S479 00 -207trans- trans-2-(4-M ethoxyh enl)- 4 -(l.3-benzod ioxo I-6-Yl) 14 (NproDVI.1Ndiethylamiflocarbonylalmiflo'ethyllPyrroldine3carboxylic 00 The title compound was prepared using the procedures described C\ in example 61, substituting propylamine for aqueous methylamine in Example 61 B and diethylcarbamyl chloride for' isobutyryl chloride in Example 61C. NMR (CD 3 OD, 300 MHz) 8 0.74 3H, 1.09 6H, 00J=7), 1.33 (in, 2H), 3.17 4H, 3.78 3H), 4.04 (in, I1H), 5.93 (s, 2H), 6.86 I1H, 7.06 (dd, 1H, 6.94 2H, 7.04 1H, 7.40 2H, MS (DCI/NH3) mlz 526. Anal calcd for

C

29

H

39 N306 0.1 TFA: C, 65.31; H, 7.34; N, 7.82 Found: C, 65.33; H, 7.43; N, 8.14.

trans- trans-2-(4- Methoxyphefl)l 4 ben zo dioxol- 5-yi) 13,5dimethylpileridinyl- carbonylmethyll-pyrrolidine-3-carboxylic acid.

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

trans -trans-2 Methoxyph efl)fl 4 ben zodi oxol- 5-yfl -1 -1 N.Ndi(s-butyl)aminocarboflylinethyll1pyrrolidine3carboxylic acid.

The title compound was prepared using the procedures described in example 1. NMR (CD3OD, 300 MHz) suggests a mixture of isomers. 8 0.83 6H, 1.27 6H, 1.6 (in, 2H), 3.79 3H), 5.93 2H), 6.75 I1H, 6.86 I1H, 6.94 2H, 7.03 1 H, J=2), 7.35 2H, MS (DCI/NH3) in/z. 511.

WO 99/06397 WO 9906397PCT/US9815479 00 -208- Example 23 trans-trans-2-(4-MetoxyohenYfl-4-( 1.3-benzodioxol-5-yl)-l1-rN-(2- Methylphenyfl-N-buitylamlilO carbonylmethyll-oyrrolidine-3-carboxylic 00 The title compound was prepared using the procedures described in example 1. MS (DC l/NH3) m/z 545. Anal calcd for C32H36N206 0.9

H

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

00 Example 324 trans-trans-2-(4-Methoxypheflyl)-4-(l .3-benz-odioxol-5-yf)l-rN-(3- Mgthylphenyfl-N-butylamino 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 2.8 (in, 3.14 1 H, J=1 3.3 (in, 1 3.44 (dd, 1 HO J=5,10), 3.53 (mn, 1IH), 3.60 2H, 3.79 3H), 3.82 (in, I1H), 5.93 2H), 6.74 I1H, 6.8-6.9 (in, 5H1), 7.06 1 H, 7.09 2H, 7.18 1H, 7.27 I1H, MS (DCIINH3) inlz 545. Anal calcd for C 32

H

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

trans. trans-4-( 1. 3-Benzodioxol5-yl) -2-(ben zylo2= ethl)- 1 Ndibutylaminocarboflylmethyl~ oyrrolidine-3-carboxylic acid Examgle 325A Ethyl trans. trans-4-( 1.3-Benzodioxol-5yl-2-(benlZ~oxymethVIV 1 N-di(nbutvl)am inocarbonvlmethylo1yrrolidine-3-caroxylate The procedures of Example 1 A-i D were followed, substituting ethyl 4benzyloxy-3-oxobutyrate for 4-methoxybenzoylacetate in Example 1A, to afford the title compound as a colorless oil. TLC (30% EtOAc-hexane) Rf 0.18; 1H NMR (CDCI3, 300 MHz) 8 0.88 J=7Hz, 1. 17 J=7Hz, 3H), 1.20-1.34 (binm, 4H), 1.40-1.56 (br m, 3H), 2.85 J=8Hz, 1 2.98-3.30 (mn, 5H), 3.39-3.60 (in, 3H), 3.64- 3.75 (in, 3.92 J-l14Hz, I1H), 4. 10 (two overlapping q, J=6.SHz, 2H), 4.53 (s, 2H), 5.91 (mn, 2H), 6.69 J=9Hz, 1 6.77 (dd, J=1.5, 9Hz, 1 6.91 1 MS (DCI/NH 3 Wne 553 WO 99/06397 WO 99/06397PCTJ/US9815479 00 -209- Exmple 325B trans. trans-4-( 1.3- Benzodioxol5.yl)-2-(benzyloXymethyfl-1 N-di(n- CI butyl)am inocarbonylmethylpyrroidilB-3-carboxylic acid The title compound was prepared according to the procedure of Example 00 71 C, as a colorless glass. TLC MeOH-CH2CI2) Rf 0. 13; 1 H NMR (CDC13, 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, I1H), 3.88-4.40 (br m, 6H), 4.45 (AB, 2H), 5.90 2H), 6.70 J=8Hz, 1H), 6.84 (dd, J=1,8Hz, 1H), 6.93 J=lHz, 00 1H), 7.28-7.39 (in, 5H); MS (DCI/NH 3 W/e 524 Exanaple 26i trans. trans-4-(1I.3. Benzodioxol5-yl)-2- (hyd roxyflethyl)- 1 N-di(nbutylaminocarbonylmlethyl)12yrrolidine-3-ca rboxylic -acid Exampe 26A Ethyl trans. trans-4-( 1.3-Benzod ioxol-5-yl)-2- (hydroynethyl) 1 N-di(nibutyflam inocarbonylmethyflo1yrrolidine-3-carboxylate The resultant product from Example 325A (128 mng, 0.232 inmol) and 25 mg of 20% Pd(OH) 2 on charcoal in 7 mL EtOH was stirred under 1 atm hydrogen for 48 h. The mixture was filtered through a plug of celite, and the catalyst was washed with 2 x 10 mL EtOH, then the combined filtrate and washes were concentrated under reduced pressure to afford the crude product. Purification by flash chromatography (40%EtOAc-hexane) provided the title compound.

Eape36 trans. trans-4-( 1.3-Benzodioxol5-yl-2-(hydroxymlethyI)- 1 Ndi(butyflam inocarbonylmethyl~yrrolidine-3-carboxylic acid The title compound was prepared according to the procedure of Example 71 C.

Examl2Z2 trans. trans--4-(1I.3-Benzodioxol.5-yI)-2-(N-mlethylprolenaiid3-Yl)1 .N-diWn- .butyflainncarbnylmethyfl~pvrolidine-3-crboxylic acid WO 99/06397 PCTIUJS98/1 5479 00 -210- Example 27A Ethyl trans. trans--4-(1 .3-Benzodoxol-5-yi)-2-(formyl)-1 ci butyl~aminocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is made by selective oxidation using the Swern 005 oxidation with DMS0, oxalyl chloride, ethyldilsopropylamine or using the Dess- Martin periodinane) of the compound of Example 326A.

Exampl 27B 00 Ethyl trans. tmans--4-(1 .3-Benzodioxol-5-yl)-2-(O-tert-butylpropenoat-3-yl-1

N-

0 10 d i(n-butyl) am inoca rbonylmrnethyl) pyrrolid ine-3-ca rboxylate The title compound is produced by condensing the compound of Example 327A with tert-butyl triphenylphosphoranylidine acetate in CH 2

CI

2 solution.

Examl 27C Ethyl trans. trans--4- 1.3- Ben zodioxoI- 5-yl) (propen oi c acid-3-yl)- N-di(nb utyl) am i noca rbonylm ethyl)pyrrolid ine-3-carboxyl ate The title compound is produced by reacting the compound of Example 327B with triflucacetic acid in CH 2

CI

2 Exampi 27D Ethyl trans. trans--4-(1I.3-Benzodioxol-5-yl)-2-(N-methylnropenamid-3-yl)- 1 Nd i(n-butyflam inocarbonylm ethyl) pyrrolid 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 Nethyl-N-(3-dimethylam ino)propylcarbodiimide, DCC).

Example 27E trans. trans--4- (1 Ben zodioxol-5 (N -m ethylipro pen am id-3-yll- 1 N-di(nibutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 327D with lithium hydroxide according to the procedure of Example 71C.

Example 28 trans. trans--4- (1 Ben zodioxol-5-yl)-2-( 1 -hydroxy-2-p ropen-3-yi)- 1 N -d i nbutyl)aminocarbonylmethyflpyrrolidine,-3-carboxylic acid WO 99/06397 WO 9906397PCTIUS98II 5479 00 -211- Ethyl trans. trans--4- 1 3-Benzod ioxo 1-5-yl)-2- (1 -hyd roXY-2 -prope n-3-yl 1 N- di (n b utyl)am inoca rbonyl meth yl)pyrrol id ine-3-carboxyl ate The title compound is produced by reacting the compound of Example 327C with borane methyl sulfide complex.

00 0 trans. trans--4-(1 .3-Benzodioxol-5-yl)-2-( 1 -hydrox-2-propen-3-YP)- 1 N-di(n- 00 butyl~aminocarbonylmethyl)pyrrolidine-3-carboxylic acid 0 The title compound is produced by condensing the compound of Example 328A with lithium hydroxide according to the procedure of Example 710.

trans. trans--4-(1 Ben zod ioxo 1-5-yl)-2- (N -ben zyla minom ethyl)-1 N-di(nbutyflaminocarbonylmethyl)pyrrolidine-3-carboxylic acid Ethyl trans. trans--4- (1 Benzodioxol-5-yl)-2-(N-benzylam inom ethyl)- 1- N-di~nb utyflam inocarbonyl methyl) pyrro lid ine-3-ca rbo Xylate 0 The title compound is produced by condensing the compound of Example 327A with benzylamine in the presence of sodium cyanoborohyd ride in ethanol.

Examle29B trans. trans--4-(1 -3-Benzodioxol-5-yfl-2-(N-benzylaminomethyh)-1 N-di(nbutyl) am inocarbonylm ethyfl)pyrrolidi ne-3-ca rboxyl ic acid The title compound is produced by reacting the compound of Example 329A with lithium hydroxide according to the procedure of Example 71C.

Examle33 trans. trans--4-(1 .3-Benzodioxol-5-yfl-2-( N-acetyl-N-benzylam inomethyfi-l1-(N.Ndi (n-butyl)am inocarbonylm ethyl) pyrrol idine-3- cgrboxyl ic acid Examle33A Ethyl trans, trans--4- (1 .3-Ben zo dioxol- 5-yi) (N -acetyl- N-benzyla min o methyl)- 1 N-di (n-b utyflam inoca rbon yl met hyflpyrro Iid ine-3-carboxyl ate The title compound is produced by reacting the compound of Example 3294A with acetic anhydride in the presence of pyridine or triethylamine.

WO 99/06397 PCT/US98/15479 00 -212trans. trans-4-( 1 .3-Benzodioxol-5-yi.2-(N-acetyl-N-benzylam inomethyl)- 1 di(n-butyl~aminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 330A 00 with lithium hydroxide according to the procedure of Example 71C.

Example 331 00 trans. trans--4-(1 .3-Benzodioxol-5-yl)-2-(ethynyl)-1 -(N.N-di(no butyl)aminocarbonylmethylpyrrolidine-3-carboxylic acid Example 331 A Ethyl trans. trans--4-(1 .3-Benzodioxol-5-yfl-2-(ethynyl)-1 -(N.N-di(nbutyl)am inocarbonylmethyl)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.

Examplp, 331 B !o trans. trans--4-(1 .3-Benzodioxol-5-yfl-2-(ethynyfl-1 -(N.N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid The title compound is produced by reacting the compound of Example 331A with lithium hydroxide according to the procedure of Example 71C.

Example 332 trans. trans--4-(1 .3-Benzodioxol-5-yl)-2-(1 -oentynyl)-1 N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylic acid Example 332A Ethyl trans. trans--4-( 1 .3-Benzodioxol-5-yl)-2- (pentyayl- 1-(N.N-di(nbutyl)aminocarbonylmethyl)pyrrolidine-3-carboxylate The title compound is made by palladium-catalyzed coupling of the compound of Example 206A and propyl iodide, employing the procedure of Taylor, et. al. Org. Chem. 1989, 54(15), 3618-24).

WO 99/06397 WO 9906397PCT/US98/15479 00 -213- ExamQJle332 trans, trans--4-( 1.3-Benzodigxol-5-yi)-2-( 1 -pentynyl)-1 N-di (n- CI butyl~aminocarbonylmethyl)pyrrolidine-3-carboxyic acid The title compound is produced by reacting the compound of 00 Example 332A with lithium hydroxide according to the procedure of C Example 71 C.

Exmpe03 00 trans-trans-2-(4-Methoxihenyfl-4-(1 .3-benzodioxol-5-yf)l- dioxopiperidinyfl ethyl)- pyrrol idi ne-3-carboxyli c acid- The compound of example 61lA 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 I D.

Examl 34 trans-trans-2-(4-Methoxyphenyl)-4-(1 .3-benzodioxol-5-yfl-1 -FN.Ndinhenylaminocarbonylmethyll-pDyrrolidine-3-carboxylic acid.

The title compound was prepared according to the procedures described in Example 1. IH 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, 2)e 6.71 1, J 6.84 (in, 7.04 1, J 7.14-7.16 (in, 6), 7.19-7.34 (in, MS (DCI/NH3) in/z 551; Anal Calcd for

C

33

H

30

N

2

O

6 65H 2 0.0.35C2HSO0COCH3: C, 69.77, H, 5.77, N, 4.76. Found: C, 69.75, H, 5.55, N, 4.64.

trans- trans--2-(4-M~ethoxyphenyl)-4-(1 3-benzodi oxol-5-yl)-1 diisopropylaininocarbonytlmethyll-pyrrolidine-3-carboxylic acid.

The title compound was prepared according. to the procedures described in Example 1. 1 H NMR (300 MHz, CD3OD) 8 0.95 3, J 1.24 3, J 1.30 6, J 2.85 1, J 12.5), 3.04 (dd, 1, 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, WO 99/06397 WO 9906397PCTIUS9S/I 5479 00 -214- J 7.35 (in, MS (DOI/NH 3 m/z 483. Anal Calcd for C27H- 34

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.

Exmpe 3 00 5 trans, trans-2-(3-Fluoro-4-methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)- 1 -(2-N-propyl-N-butanesulfonylaminoiethyfl-pyrrolidine-3-carboxyi*C 00 Using the procedures described in Example 313 and Example 66, 0 ~the title compound was prepared as a white solid. m.p.65-66 0 C. 1 H NMVR Ni 0 (CDC13, 300MHz) 8 0.82(t, J=7.5Hz, 3H), 0.92(t, J=7.5Hz, 3H), 1.34- 1 .52(m, 4H), 1 .72(quintet, J=7.5Hz,2H), 2.25-2.35(m,l1H), 2.72-2.94(m, 2.97-3.12(m, 2H), 3.19-3.46(m, 2H), 3.44(d, J=gHz,IH), 3.53- 3.60(m, 3.67(d, J=9Hz, 1H), 3.89(s, 3H), 5.95(s, 2H), 6.74(d, J=8Hz, 6.82(d, J=8Hz, 1H), 6.92(t, J=9Hz, 1H), 6.97(s, 1H), 7.12(d, J=9Hz, 7.18(d, J=l2Hz, 11H). MS (DCI/NH3) m/e 565 Using methods described in the above examples, the compounds !0 disclosed in Table 1 can be prepared.

H

3

C

MOOH

Table 1 R R R O2N4%% H2NJO 1.2. 3.

WO 99/06397 WO 9906397PCT/tJS98/1 5479 00 00 4.

7.

c0'0 13.

0 0 16.

00o -215- Table 1 cont.

R

o0 6.

00o HCOOtY 14.

OA

17. 18.

02~ 0 19. WO 99/06397 PCTIUS98/15479 o 0 22.

H

3 Cog 0 0 28.

FH2CCc;;E

F

2 0 0 31.

F

2

HC..

F

2 0 0 34.

0 0 -216- Table 1 cant.

R

0 0 23.

0 0 26.

FH

2 k,/ 0 0 29.

FH

2

C.

F

2 0 0 32.

F

3

C,

F2P 0 35.

Ip 0 0 0 0 24.

F

3 0 0 27.

FH2 0 0

F

2 0 0 33.

F3"O

F

2 0 *0 36.

F3C--'K.

0 0 37. 38.

WO 99/06397 PCT/US98/15479 -217- Table 1 cont.

R

00 00 0 d, 0 43.

c 46.

49.

0 52.

0 58.

F3001%% 41.

6'o 44.

47.

47.

F30

N

0 42.

H3%#T K do (9v 48.

53.

56.

/OK

0 59.

Q

0~~6 54.

57.

0 WO 99/06397 WO 9906397PCT/US98/1 5479 0 61.

64.

0 6.7.

-218- Table 1 cont.

R

62.

65.

68.

71.

63.

0 66.

69.

72.

78.

73.

76.

0 74.

0 77.

WO 99/06397 WO 9906397PCT/US98/I 5479 -2 19- Table 1 cont.

R

80.

79.

H

3 c0 r laK

N,^

81.

88.

86.

89.

84.

87.

Ak 92. 93.

94. WO 99/06397 WO 9906397PCT/US9815479 0 97.

1.00.

0 103.

-220- Table 1 cont.

R

98.

101.

0 104.

107.

CH

3 0 102.

0 08 0 0 106.

CH3 2 109.

112.

110.

ill.

113.

d'0 0Nr 114.

-oo, 0 115. .116.

117.

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 00 118.

121.

124.

-22 1- Table 1 cont.

R

0T 119.

122.

120.

123.

126.

129.

125.

127.

128.

OCH

3 131.

130.

132.

133. 134.

135.

WO 99/06397 WO 9906397PCTIUS9815479 -222- Table 1 cont.

R

137.

d 0 136.

139.

140.

138.

141.

144.

147.

c0 142.

145.

148.

H

3

CY

0 0 00 14.

00 149. 150.

0rr 151. 152.

153.

WO 99/06397 WO 9906397PCT/US98/1 5479 -223- Table 1 cont.

R

154.

0 157.

R

9 155.

0 0 158.

R

0 156.

0 159.

160.

163.

69y; 161.

164.

167.

162.

165.

00 166. 168.

WO 99/06397 PCT/US98/15479 169.

Y

0 0 172.

00 175.

00 178.

F

3 0 0 181.

H200> 00 184.

-224- Table 1 cont.

R

y 0 0 170.

0 0 173.

Y

FF

0 0 176.

0 0 179.

0 0 182.

8o 185.

Y

171.

o~ 174.

0 0 177.

F3O F F 0 180.

0 0 183.

00 186.

F F 0 Obr 0COO d 0

H

3 C0*>

F

3 -g 00 187. 188. 189.

WO "/06397 WO 9906397PCT/US98/1 5479 -225- Table 1 cont.

R

Haco>o,, 190.

191.

193.

0~$ 196.

199.

202.

00~o,- 194.

0 0 197.

200.

203.

y 192.

195.

A3 ,S 198.

201.

204.

Kr 205.

206.

207.

WO 99/06397 PCTIUS98/15479 -226- Table 1 cont.

R

208.

y )rA 211.

V

214.

H %yfl 217.

HV

210. 209.

212.

215.

218.

CF3 O ri 213.

I ?H 216.

219.

~F

3 3:F yo 220. 221.

222.

WO 99/06397 WO 9906397PC/US9815479 -227-

R

223.

93V 226.

229.

V

232.

235.

Table 1 cont.

R

9F 3

Y

224.

227.

y 230.

CAY

233.

y 236.

R

PF

3 225.

228.

231.

234.

237.

I

WO 99/06397 PCT/US98/I5479 -228-

R

A..r- Nyr 238.

y 241.

V

244.

247.

V

FO

250.

Table 1 cont.

R

239.

242.

R

PV"r 4 240.

(I-

243.

246.

249.

252.

245.

248.

251.

WO 99/06397 PCT/US9S/1 5479 "yr~ 253.

V

256.

259.

-229- Table 1 cant.

R

y NC,N~r,4 254.

257.

255.

258.

Ke- 260.

261.

NyO Y 0 262.

263.

264.

Y

N 0 265. 266.

K

N 0 267.

I

WO 99/06397 PCTIUS98/15479 268.

Ad Nr 271.

274.

277.

N-0 280.

-230- Table 1 cont.

R

269.

Ny- 272.

275.

%N 0 278.

Il ll 9F3 NtrV 270.

cNv 273.

N

276.

N O 279.

282.

281.

WO 99/06397 PCT/US98/1 5479 -231- Table 1 cont.

R

1Ysc 283.

286.

289.

292.

y 295.

284.

287.

V

N 0 290.

293.

296.

285.

288.

N O 291.

294.

N00 297.

WO99/06397 PCT/US98/15479 -232- Table 1 cont.

R

V

NN0 298.

301.

304.

307.

307.

299.

I-r y 0 302.

305.

(rIN^ N 0* NY0 300.

y 303.

3 Ny0 306.

308. 309.

LK-

y N 0a'~ 310. 311.

312.

I

WO 99/06397 PCTIUS98/15479 -233- Table 1 cont.

R

V

314.

N 0 313.

K

1 316.

o 319.

322.

b~C~~f0 '0, 315.

318.

317.

320. 321.

323.

7 324.

K>

325. 326.

327.

WO 99/06397 PCTIUS9/15479 -234- Table 1 cont.

R

Io 328.

329.

331.

332.

335.

A"or 330.

333.

V

336.

339.

Ny 334.

337.

340.

338.

341.

342.

WO 99/06397 PCT/US98/15479 -235- Table 1 cont.

R

343.

I %r 346.

cA

N

349.

352 352.

344.

V

347.

V

IYN

350.

353.

353.

N

y 345.

348.

348.

351.

V

354.

355. 356.

356.

357.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -236- Table 1 cont.

R

358.

359.

361.

362.

360.

V

363.

366.

364.

365.

367.

370.

368.

N

371.

368.

372.

WO 99/06397 PCT/US98/15479 -237- Table 1 cont.

R

374.

y 373.

376.

377.

375.

378.

y 381.

Kr My 379. 380.

382.

383.

I>

384.

385. 386. 387.

WO 99/06397 PCT/US98/1 5479

N

388.

391.

394.

397.

400.

-238- Table 1 cont.

R

y 389.

V

392.

)y 390.

393.

396.

395.

398.

399.

401. 402.

WO 99/06397 PCT/US98/15479 -239- Table 1 cont.

R

403.

406.

409.

412.

415.

404.

407.

410.

413.

416.

408.

411.

414.

417.

405.

WO 99/06397 PCTILS98/15479 -240- Table 1 cont.

R

COOEt 419.

V

418.

'COOEt COOEt 421.

N02 424.

CN

427.

V

430.

422.

N0 2 425.

COOM

420.

N

NO

2 423.

V

NO

2 426.

N

V^CN

429.

0 24

UCN

428.

Nl: 431.

I'D.

WO 99/06397 PCTUS98/1 5479 -241- Table 1 cont.

R

R

433 0 436.

00" 439.

442.

445 445.

434.

0 437.

440.

443.

446.

R

0 435.

438.

441.

444.

447.

WO 99/06397 WO 9906397PCT/US98/15479 448.

451.

V

454.

moo 0 457.

-242- Table 1 cont.

R

449.

y Xf N 452.

$crN0 450.

453.

0 456.

455.

moo 0 458.

0 459.

0 462. 460. 461.

WO 99/06397 WO 996397PT/US981 5479 -243- Table 1 cont.

00 00 463.

464. 465.

466.

467. 468.

471.

469. 470.

372.

474.

473.

Yc4 477.

475. 476.

WO 99/06397 PCT/US98/ 5479 00 00 0 478.

0 481.

0 484.

0 487.

F I0 0 -244- Table 1 cont.

R

C4 479. 0 0 482.

0 480.

483.

486.

485.

Fo 'F8x 0 488.

489.

490. 491.

492.

WO 99/06397 PCT/US98/1 5479

F

493.

0 496.

499.

o4 0 502.

505 505.

-245- Table 1 cont.

R

0 494.

0 497.

500.

500.

495.

0 498.

501.

503.

0 504.

M.O

OMA 0 507.

6 506.

WVO 99/06397 PCT/US98/1 5479 OM. 0 508.

-246- Table 1 cont.

R

OMo 0 509.

M

o9 ARr OMe 0 512.

OMo aM. 0 515.

OMe 0 518.

0Me 0 510.

OM. 6 513.

511.

OMO 0 514.

moo aMe 0 517.

516.

519.

OM. 0 520.

521.

522.

WO 99/06397 PCTIUS98/I5479 523.

0 526.

8r~Nb4 529.

Br~Nyf0 532.

535.

-247- Table 1 cont.

R

Moo%- 524.

B0 527.

y 530.

533.

536.

me 525.

528.

531.

534.

537.

WO 99/06397 PCT/US98/1479 y 538.

N

540.

"o 544.

547.

V

550.

-248- Table 1 cont.

R

y 539.

542.

545.

548.

551.

540.

Ny 543.

y 546.

549.

552.

WO 99/06397 PCT/US98/15479 553.

N

556.

Or 559.

y 562.

565.

-249- Table 1 cant.

R

y 554.

F

CI

557.

nil 560.

ly 563.

AF&O

rl

K

555.

v 558.

Orv 561.

564.

F>)

566.

567.

WO 99/06397 PCT/US98/1 5479 -250- Table 1 cont.

R

R

F

FD 0 568.

FY(J

571.

FV

574.

oo, r 577.

0 580.

0 583.

R

F7Y 570.

569.

572.

575.

y 0 578.

0 581.

0 584.

573.

0 576.

I-r 0 579.

0 582.

(2L 0 585.

WO 99/06397 PCTLS98/1 5479 -251-

R

0 586.

589.

y v 592.

595.

598.

601.

Table 1 cont.

R

0 587.

590.

593.

vrd~ 596.

599.

602.

R

0 588.

591.

594.

N-

597.

600.

603.

WO 99/06397 WO 9906397PCT/US98/15479 -252- Table 1 cont.

R

H

0 604.

605.

606.

-0 609.

607.

608.

610.

i. 0 611.

614.

612.

H

IV"

615.

613.

H

617.

616.

618.

619.

621.

620.

WO 99/06397 PCT/US98/15479 -253- Table 1 cont.

R

624.

622.

623.

625.

627.

626.

628.

631.

634.

y 0 1& 0 629.

r

WH

632.

635.

K

630.

H

633.

a4 636.

639. 637. 638.

WO 99/06397 PCT/US98/15479 640.

0 643.

646.

-254- Table 1 cont.

R

V

641.

0 644.

0 642.

0 645.

0 648.

647.

6y 650.

649.

652.r 0 652.

651.

0 653.

654.

WO 99/06397 WO 9906397PCT/US98/15479 -255- Table 1 cont.

R

V

657.

655. 656.

658.

659. 660.

662.

661.

664.

663.

665.

666.

667. 668. 69 669.

WO 99/06397 WO 9906397PCTIUS98/115479 -256- Table 1 cant.

R

670.

%WVA

673.

01 672.

671.

674.

675.

677.

676. 678.

679.

680.

681.

K0 682. 63 683.

684.

WO 99/06397 PCT/US98/15479 -257- Table 1 cont.

R

685.

'ocr 688.

691.

694.

694.

ai 01

V

scYX 687.

687. 686.

689.

690.

692.

693.

695.

MoO-Cy0 698.

696.

Mooj() 607.

699.

WO 99/06397 PCT/US98/15479 -258- Table 1 cont.

R

M701.

701.

H

700.

o 703.

F A 706.

o 0 709.

712.

715.

715.

0 702.

704.

707.

705.

0 708.

oo 711.

710.

713.

713.

0 0 714.

WO 99/06397 -259- PCT/US98/15479 Example 338 Using methods described in the above examples, compounds comprising a parent structure selected from those disclosed in Table 2A and an R substituent selected from those disclosed in Table 2B can be prepared.

Table 2A

MOM

2

COOH

R-2.

u? H3

OICOOH

3.

3.

CH

3

R-

MOM

R

COOH

0 -7 WO 99/06397 WO 9906397PCTIUS9BII 5479 -260- Table 2A cant,

H

3

,OOH,

12.

OCH

3

.OCH

3 OCH 3

-OCH

3

H

3

,COON

Fl-NV 0>

OCH

3 17.

MOM

19. OCH3 C0

COON

F

Fl-N

*ICOON

21. 0 WO 99/06397 WO 9906397PCT/US9815479 MoMCOOH 22. 0 m m m

COOH

I&

R-OOOH

28.1 -261- Table 2A cant.

CH

3

,COOH

23. 0

CH

3 26. 0 3 R

#COOH

NN)

cOON

F

.COOH

27. 0

F

R-

COOH

29.

F

OCOOH

N'

WO 99/06397 WO 9906397PCT/US9S/I 5479

MOM

%34.

M7OM '37.

OCOOH

MOMH

OCH

3 43.

-262- Table 2A cont.

3

#COOH

CH

3 R-ti 38. OCH 3

OHCH

41.

.OCH

3

.COOH

WO 99/06397 WO 9906397PCT/US98/15479 00 00 mom

.COOH

46. o~ 49.

-263- Table 2A cont.

CH3 pCOOH R- 4CO 47.

O.COOH

R-

53.

F

R .COOH 48.

.4COOH* 51.

R-

54.

._COOH

OCH

3

OCH,

WO 99/06397 WO 9906397PCT/EJS98/1 5479 -264- Table 2A cont.

*,COOH

61.0 R

*COOH

69.

WO 99/06397 WO 9906397PCT/US98/1 5479 -265- Table 2A cont.

00 ~COOH 00 QH3

OCH

3

CH

3 H300 L COOH 0

H

3 0

COH

#PCOOH

76.

c H 3 R-

%COOH

79.

R- 000OH j'0 77.

13

COH

78. r 00014 WO 99/06397 WO 9906397PCT/US98/I 5479 00 -266- Table 2A cont.

CH3

H

3

H

3

CC

H

00 OH

ONN

q~PCOH R- .COO pr O OCH

R-

0

OCH

3 89.

92. 93.

93.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -267- Table 2A cont.

H

3

OH

3 000 R- CO 94. 00

F

e11 ~OCH 3 96. I 103. 14 104.

105.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -268- Table 2A cont.

109.

OCOOH

112.

*.COOH

115.

R-t6,CO00H

,COOH

113.

R-

.~COOH

116. 0

COOH

R-

,CO

H

3 F

.COOH

SOCH

3

OCH

3 R- '00 114.

R-

117. -0 120.

118. 119.

WO 99/06397 PCT/US98/15479 00 121. 0 00 CH3 -269- Table 2A cant.

122.

H

3

*.COOH

RO

125.

OCOOH

R-

O

128.

123.

R-

126.

R-

o 127.

OCOOH

R-s 0 129.

132.

130. 131.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -270- Table 2A cont.

133.

137.

0CH 3 R-N

O.COOH

140. 0

CH

3

,.COOH

R-0 143. I

CH

3

COOH

141.

ON

OCHH

COOH

H3CO ;t 144.

142.

WO 99/06397 WO 9906397PCTIUS98I1 5479 -271- Table 2A cont.

GCOOH

145.

F

148.

F

.COOH

151. 00H 3 146. -4.Nt

CH

3

CH

3

F

F+ fCOOH

H

3 CO

OCH

3 149.

150.

152.

OMOM

H 3 C OCH 3 156.

154. 155.

WO 99/06397 WO 9906397PCTIUS98II 5479 00

COOH

00 9CH3 -272- Table 2A cont.

158. F

H

3

H

3

.OCOOH

Ha OCH3 161.

162.

164.

163.

165.

F

N

167. 0

MO

H

168. 0 166.

WO 99/06397 WO 9906397PCT/US98/15479 -273- Table 2A cont.

F

'Q

1 69.

MOLA

172. 0

F

H

171.

MOMO

H

R )N 174.

F

H

F

177.

R-

176.

175.

mom

H

1 78.

*OCH,

179.

180.

WO 99/06397 WO 9906397PCT/US98/1 5479 -274- Table 2A cont.

c-I F 00 R-

N

000 c-I

H

3 cX 182.

H

3 183. 0 186. 0~

F

olt CH3 R H 189. 0 0)t N& S CH RA- H C 192.

188.

190. 11 191.

WO "/06397 WO 9906397PCT/US98/15479 00 -275- Table 2A cont.

FF

CF MO FM 009&.10 R- A- HC PC FH R- H 3

NOH

197.93. 194.19. OH 0 /o prH 3- 3 H 3 Fl-H CF 9. 200. 20. 0 NS- N(CH3 2

H

202. 202. 203. 24 204.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -276- Table 2A cont.

206.

207.

205.

VCH

3 208.

209.

210.

H

3

OOOOH

211.

OCH

3

H

3 OCI4 3 h 0 eCOOH 0 214.

OCH

3

F

OCOOH

215.

OCH

3

H

3 0) 213. OCH 3 0 216. 0CH 3 WO 99/06397 WO 9906397PCT/US98/15479 4 0COOH

OCH

3 217.

E,

,,COOH

0 220.

EtO 223.

r-% 0 00 226.

-277- Table 2A cant.

EtO

OCOOH

FA- Qi) 218.

EtO F 1

.COOH

Ft- 221.

EtO F eCOOH

OCH

3 224.

O00 227.

Ea

FA-

'0 219.

E F

,COOH

Al- 222.

0

,COOH

0a 225.

228.

WO 99/06397 WO 9906397PCTIUS98I1 5479 -278- Table 2A cont.

00 00 229.

ri H 3 10CH 3 4 9

COOH

232.

230.

H30 OCH 3 eCOOH 233.

H

3 1OCH 3

.,COON

236.

COOH

239.

00 aC0H Oo) 231. OCH3

H

3 10CH 3 '0 234.

H

3 0 OCH 3

.OONH

0) 237.

H

3 C OCH 3

.Q)

238.

OCH

3 'cOOON R/0 240.

WO 99/06397 WO 9906397PCT/US98/15479 '0

COOH

R'%

241.

,.COOH

H

3

F

'1 0 247.

H

3

F

250.0 -279- Table 2A cont.

R-N

242.

'DOH

243.

H

3

J.,COOH

246. 245.

O>CH

3

H

3

F

COOH

248.

H

3

COOH

RN

C

251.

249.

252.

WO 99/06397 WO 9906397PCTIUS98/15479 -280- Table -2A cont.

FcQ 253.

Fq

,OCOOH

256.

254.

259.

F

4

.OOOH

257.

9

COON

260.

263.

J,COOH

266. OCH 3 F F 255.

COOH

~C)

258.

J.COOH

0 261.

,ecoOH 264.

F

267.

J

262.

C0H Fr0) 265.

WO "/06397 WO 9906397PCTIUS98/I 5479

COCH

0 268.

271.

~C00 274.

,c:OOH %Ft' 277.

-281- Table 2A cont.

J,,COOH

'0 269.

4

OOH

272.

,COON

it/0 0 275.

270.

273.

OCH

3 276.

278. 29 279.

WO 99/06397 WO 9906397PCT/US98/1 5479

,COOH

0) 280.

OCH

3 -282- Table 2A cont.

q,COOH 281.

,OWOH

284.

C

COOH

0 290.

283.

J.,OOH

K')

286.

0 282.

1,,COON 285.

288.

JCOOH

291.

289.

OCH

3 292.29.24 293.

294.

WO 99/06397 WO 9906397PCT/US98/15479

,COOH

295.

eCOOH

/OO

-283- Table 2A cont.

,OOOH

il 0 296.

,OOH

~0 298.

299.

.COOH

297.

q

IJ#COOHC

300.

303.

306.

301. 0CH3 304.

302.

305.

WO 99/06397 WO 9906397PCTIUS98/I 5479 307.

-284- Table 2A cont.

.COOH

0'0 31.

309.

309.

312.

310.

313.

.,COOH

316.

OCOOH

R-

315.

317.

318.

J

.,COOH

R- 1 0 J1.320. 31 321.

WO 99/06397 WO 9906397PCT/US98/1 5479 -285- Table 2A cont.

.COOH

323.

0

.COOH

322. OC&4 3 324.

0 h' 326. 327.

325.

328.

ooOH '*H0 331.

4 ~0H 334.

'00 .COON

C

329.

OH

,COOH

332.

COON

335.

-1.COON

R,

330. OCH3 cOOH 333.

336.

WO 99/06397 PCT/US9115479 f4

.COON

00 337.

-286- Table 2A cent.

,COOH

£4> 338.

r x 341.

4COOH 344.

347.

340.

0 343.

339.

COOH

*COOH

0 342. ocH 3

COOH

345.

COOH

348.

346.

0

,LCH

3

-N

H

349. OCH 3 350.

351.

WO 99/06397 WO 9906397PCT/US9815479 -287- Table 2A cont.

00 A 0 -CH 3 305* OCH 3 H3H /0 143, 0 0

OCH

3

EIO

0 R' /0 35. OCH 3 358.

0 0 0 361. OCH 3 363.

362.

WO 99/06397 WO 9906397PCT/US98/15479 -288- Table 2A cont.

364. 365.

H

3 \o F 367.

H

3 /Q,2J CH3 366.

H

3 C, t A NH 369.

H

3

N

0) 372.

368.

H

3 h WNH R/0 370.

H43 W. I.NH H43 tajNH /0 371.

0 R- 0 373. 374.

375.

WO "/06397 WO 9906397PCT/US98/1 5479 -289- Table 2A cont.

00 00 377.

378.

376.

381.

379.

380.

WN"NH

382.

'0

NH

383.

384.

tNH 387.

385. 386.

WO 99/06397 WO 99/6397 CT/US98/1 5479 -290- Table 2A cont.

388.

~NH

391.

F

3

,COOH

WN~

0 394.

F

3

.COON

397.

389.

F

3

,COOH

392.

F

3

.,POOH

395.

F

3 1 1

COOH

/0

OCH

3 398.

390.

F

3

COOH

0 393.

396.

F

3

CF

2 ~C0H 399.

WO 99/06397 WO 9906397PCT/US9815479

F

2

CF

3 '0) 400.

kF 2

CF

3

,COOH

N 403.

1F 2

CF

3 1 00

OCH

3 406.

4

COOH

409.

-291- Table 2A cont.

F

2 CF3 0 401.

kF 2

CF

3

*COOH

kF 2

CF

3 405.

4 1

COOH

407. 408.

411.

410.

412. 43 413.

414.

WO 99/06397 WO 9906397PCT/US98/I 5479 -292- Table 2A cant.

416.

415.

z .COOH 418.

417.* 419.

'COOH

420.C 0 01 423.

421.

422.

.00014 R-N i 14 &0 424.

*COOH

/0 427.

425. 426.

428.

429.

WO "9/06397 PCTIUS98/15479

COOH

430.

COOH

433.

4 .OO

H

436.

-293- Table 2A cont.

000H 0 431.

OCOOH

434.

434.

432.

'o'0

'.COOH

Ft435 435.

438.

437.

441.

439.

ecooH 442.

440.

444.

443.

I

WO 99/06397 PCT/US98/15479 -294- Table 2A cont.

IOO

446.

(*ON

445.

jCOOH

~CI>

448.

R-Q&

00 451.

ROOH

450.

4.COO 453.

449.

.COOH

452.

454.

455. 456.

I

WO 99/06397 WO 9906397PCT/US98/1 5479 -295- Table 2A cont.

/0 457.

JCOOH

458.

459.

462.

460.

461.

0) '~0 463.

ICOOH

/0 1 465.

464.

WO 99/06397 WO 9906397PCT/U59815479

R

0 0 4.

0 7.

0 -ThOy 0 13.

c Oy 0 16.

o*0 -296- Table 2B

R

0~ 2.

5.

8.

0> 0 14.

H3 C eO 1 0 17.

0 0

R

0 3.

6.

9.

0 0 12.

0 0 18.

100h 19. WO 99/06397 WO 9906397PCT/US98/I 5479 00 22.

H~C0".'N^ 0 0 28.

FHA r e 31.

-0h

F

2 HQC.. NNo^ 34.

cr0 37.

-297- Table 2B cont.

R

H

3 CoQr.% 0 0 23.

H

3 C0-,o,,N 26.

29.

FH

2 C

F

2 0 6 0 32.

HC~ r% 24.

d'0 27.

FH

2 .%4

F

2 HC. N 33.

1Th F2 0

F

3

C,

F

2 00 36.

I eh ;0 d'0 41.

WO 99/06397 WO 9906397PCTIUS98II 5479 43.

46.

-298- Table 2B cont.

R

44.

47.

F

3 cQ.o 0 0 48.

49.

52.

58.

50.

53.

51.

54.

F'a 57.

cr.a 0 WO 99/06397 PCTIUS98/1 5479 -299- Table 2B cont.

R

61.

64.

7H

OCH

3 H3C 0 68.

66.

0 69.

Y1H 3 r' 00 0 0 73.

0 71.

0 74.

o

ON

72.

0 00 76. 77.

WO 99/06397 WO 9906397PCT/US98/1 5479 00 00 C7 0 79.

d 0 82.

600

Y

88.

0 0 91.

0 0 97.

300- Table 2B cont.

R

0 80.

83.

0 86.

00 89.

Y

616b F .F 98.

81.

0 0 84.

8.

00 8.

96.

99.

WO "9/06397 PCT/US98/15479 H~c0Th 100.

103.

106 0 109.

00 112.

FAfO F F 0 b -301- Table 2B cont.

R

H

3 COTh 00 101.

H3Ca*-> 00 104.

H

3

CO#>\

00 107.

00 110.

0 0 102.

105.

F F H 3 C0' 108.

111.

00 114.

00 0 0 113.

A 0 116.

115. 117.

WO 99/06397 PCT/U598/1 5479 0 0 118.

121.

.302- Table 2B cont.

R

119.

y C3,aNr *~0 120.

y-r 122.

123.

124.

y L-cr0 127.

125.

128.

OH

IV 0 126.

CQ-r N1rA 129.

130. 131. 132.

WO 99/06397 PCT/US98/1 5479 133.

136.

CF2%P 139.

qF 3

V

OovrA 142.

-303- Table 2B cant.

R

y 134.

137.

CF

3

Y

140.

0C

OHYL-

135.

9PF 3 138.

F3 11 141.

144.

143.

0( y

K

147.

145. 146.

WO 99/06397 PCT/US98/1 5479 -304-

R

148.

151.

154.

y

V

156.

160.

Table 2B cant.

R

149.

y 152.

155.

158.

R

150.

cl- 153.

Pt r^r 156.

159.

162.

161.

WO 99/06397 PCT/US98/15479 -305- Table 2B cont.

K

165.

163.

164.

166.

167.

169.

y 170.

173; y

L%

1 i rAiI 168.

171.

o 174.

K-11.

4)Cr/-r 172.

y Cx4 175. 176. 177.

WO 99/06397 PCTIUS98/1 5479 -306- Table 2B cont.

R

00 00 178.

179.

0 180.

183.

yr1 181.

182.

184.

187.

NC%yA 190.

185.

188.

191.

186.

N

189.

N

192.

WO 99/06397 WO 9906397PCTIUS9SII 5479 -307- Table 2B cont.

NY

193.

194.

195.

196.

198.

197.

199.

200.

201.

KN go- 202.

203. 204.

205. 206. 27 207.

WO 99/06397 PCTUS98/1 5479 00 00 N 0 208.

y r.%V- N 0* -308- Table 213 cont.

R

N0 209.

N 0 210.

N 0~s 211.

212.

213.

V

214.

217.

Ny 215.

K-.

216.

y

KJV

r"Y"d 218.

219.

N )O v IlN N 0~ 220. 221. 222.

WO 99/06397 PCT/US98/1 5479 223.

y- -309- Table 2B cont.

R

N 0 224.

y

V

226. 227.

225.

Y-104 228.

231.

234.

229.

232.

v 230.

2 233.

L~f jN 0 235. 236.

237.

WO 99/06397 PCT/US98/15479 -310- Table 2B cont.

R

239.

238.

240.

241. 242.

243.

244.

247.

245.

V

248.

246.

249.

252.

252. 250.

252.

WO99/06397 PCT/US98/I 5479 -311- Table 2B cont.

R

253.

254.

255.

257.

256.

259.

262.

N

265.

260.

258.

y 261.

264.

267.

263.

266.

WO 99/06397 WO 9906397PCTIVS98/1 5479 -312- Table 2B cont.

268.

269.

271.

*IIK Ny 274.

272.

R

V

270.

273.

V

276.

V

Ny 282.

275.

277.

278.

280. 281.

WO 99/06397 PCT/US98/15479 -313- Table 2B cont.

R

;N

283.

"CIN

286.

y 289.

N

292.

295.

284.

N

287.

Ny 290.

293.

296.

296.

285.

288.

291.

294.

297.

297.

WO 99/06397 PCT/US98/I 5479 -314- Table 2B cont.

R

298.

301.

304.

299.

c9--^A 302.

305.y 305.

300.

303.

306.

309.

307. 308.

Y,

N

N~S

310. 311. 312.

WO 99/06397 WO 9906397PCT/US98/I 5479 -3 Table 2B cont.

R

315.

313.

314.

316.

317.

318.

319.

322.

320.

323.

321.

324.

327.

325. 36 326.

WO 99/06397 PCT/US98/15479 -316-

R

328.

N

331.

334.

Table 2B cont.

R

329.

332.

R

v a\ 330.

N333.

333.

335.

336.

N0 339.

NO

2 342.

337.

(XNO

2 340.

338.

341.

WO 99/06397 PCTIUS9/I5479

(N

343.

-317- Table 2B cont.

R

(>CN

344.

02X 345.

02J KII-1 347. 348.

346.

349.

0 352.

350.

0.

353.

0 351.

0 354.

355.

N

356. 357.

WO 99/06397 PCTIUS98/15479 -318- Table 2B cant.

R

"4ny 358.

yr 361.

scrYr* 364.

367.

367.

359.

362.

Ir 365.

y 368.

y

Y-A

360.

N-

363.

0 366.

y 369.

0 372.

3

F

370.

371.

WO 99/06397 PCT/US98/15479 -319- 00 00 Table 2B cont.

R

373.

Mo 0 376.

IO

0 379.

382.0 382.

374.

375.

377.

380.

380.

378.

o 381.

381.

383.

384.

o 387.

385. 386.

'CL, 'CL 0 0 388. 389.

390.

WO 99/06397 PCT/US98/1 5479 -320- Table 2B cont.

R

0 392.

0 391.

0 394.

0 393.

395.

396.

397.

398.

y CIIc rA 0 399.

0 402.

0 400.

0 401.

403. 404.

405.

F

FX V 0 408.

406. 407.

WO 99/06397 PCT/US98/ 5479 -321- Table 2B cont.

R

410.

FD

0 409.

0 412.

0 415.

411.

413.

414.

405- 417.

416.

0 419. 418.

420.

421.

M 4Are 423.

OM. 0 424. 425.

426.

WO 99/06397 PCT/US98/1 5479 -322- Table 2B cont.

R

OMS 0 427.

OMe 0 430.

moo OM. 0 433.

436.

OMe 0 429.

428.

Me lOi ohmo 0 431.

M

eO~Q 0MO 0 434.

OM0 0 432.

moQ- OMO 0 435.

aMe 0 437.

438.

moo v 439.

440.

443.

441.

mo 442.

444.

WO 99/06397 PCT/US98/I 5479 445.

0 448.

451.

y 454.

N17f -323- Table 2B cont.

R

y 446.

449.

452.

y 455.

vC aN"r/_ 447.

450.

453.

456.

N-

459.

457. 458.

WO 99/06397 WO 9906397PCTIUS98/1 5479 -324- Table 2B cont.

R

460.

463.

461.

464.

467.

SBa 465.

F ICal 468.

462.

466.

469. 470.

471.

F-A CI 0 473. 473. 474.

472.

WO 99/06397 PCT/US98/15479 -325- Table 2B cont.

R

Br o 476.

Br.

F45 475.

478.

B:

481.

484.

K r 479.

V

S482.

482.

477.

U 0 480.

F>

483.

o F486.

486.

485.

0 487. 488.

489.

WO 99/06397 PCT/US98/15479 -326- 490.

yr" 0 493.

0 496.

0 499.

0 502.

505.

Table 2B cont.

R

0 491.

o 494.

0 497.

0 500.

R

0 492.

o 495.

0 498.

0 501.

0 504.

507.

503.

506.

WO 99/06397 PCT/US98/15479 -327-

R

y 508.

511.

514.

517.

520.

Table 2B cont.

R

509.

V

512.

515, 518.

R

510.

513.

y 516.

519.

522.

521.

WO 99/06397 PCT/US98/15479 -328- Table 2B cont.

R

1-60

H

523.

526.

529.

H

532.

535.

535.

525.

524.

527.

528.

530. 531.

o 533.

H

536.

534.

537.

WO 99/06397 PCT/US98/15479 -329- Table 2B cont.

R

538.

541.

544.

539.

H

542.

545.

548.

551.

540.

r 0 543.

-Jr 546.

549.

552.

547.

550.

WO 99/06397 PCT/US98/15479 00 y 00 553.

556.

-330- Table 2B cont.

R

r 554.

557.

555.

558.

561.

564.

559.

560.

562.

563.

0 565. 566. 57 567.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -331- Table 2B cont.

R

568.

571.

0y 570. 569.

572.

573.

574. 575.

576.

577.

578. 579.

580. 581. 52 582.

WO 99/06397 WO 9906397PCTIUS98/1!5479 00 00 00 -332-

R

583.

586.

V

589.

Table 2B cant.

R

584.

585.

:0 0 588.

587.

590.

591.

593.

594.

592.

595. 596. 57 597.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -333- Table 2B cont.

R

0 598.

y 601.

604.

607.

610.

599.

600.

602. 603.

605.

606.

609. 608.

611. 62 612.

WO 99/06397 PCT/US98/ 5479 r A 613.

616.

M.Oj6 619.

-334- Table 2B cont.

R

614.

617.

0.~4 620.

615.

0 618.

621.

622.

V

v x y 623.

0 0 624.

00 625. 626.

627.

WO 99/06397 PCT/US98/15479 -335- Table 2B cont.

R

629.

629.

630 630.

628.

631.

632.

632.

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

WO 99/06397 WO 9906397PCT/US9815479 -336- Table 3A

F

.,COOH

I

.COOH

4.

CH

3 R-

COOH

7.

CH

3 4COOH 5.

*COOH

0 WO 99/06397 WO 9906397PCT/US98/I 5479 -337- Table 3A cont.

CH

3

OCH

3 16.

0 0

N'CH

3

H

WO 99/06397 PCTIUS98/1 5479 -338- Table 3B 1.

0 7.

0 0 13.

0 16.

N00 0 2.

0 8.

0 0 14.

H3C Q 0 17.

00b( -h7 3.

0 6.

9.

00 12.

0 H3CQ 0 18.

00\FC' I WO 99/06397 WO 9906397PCT/U598/1 5479 22.

HaC 0.- 28.

F

2 0e 0 31.

-1h

F

2 HIC-Ce

F

2 e) 0 34.

37.

-339- Table 3B cant.

R

23.

10*0*

H

3

CQ,;N.

6' .0 26.

FH

2 Nl.- 29.

32.

24.

27.

d F2HC.

F

2 6 0 33.

-Th-

F

2 0 0 36.

F

2 0 35.

do' -Th rs" 0 o 6' WO 99/06397 PCT/US98/15479 0 0 43.

F3ooIA 46.

-340- Table 3B cont.

R

0 0 44.

0 0 47.

0 0 H3 Ca ro 0 0 48.

0 49.

52.

2y 50.

53.

51.

54.

57.

C, 0,0 56.

ULCIO 0 58. 59.

WO 99/06397 PCTIUS98/1 5479 oxC3 61.

64.

-341- Table 3B cont.

A

OCH

3 62.

68.

YH3 71.

00 o o 74.

00 H3C 0 63.

69.

72.

d'o 73.

d'o 00 o' 76. 77.

WO 99/06397 WO 9906397PCTIUS98/1 5479 79.

d o 82.

0

Y

88.

0 0 91.

Y

F3C.I 0 0 97.

-342- Table 3B cont.

R

80.

83.

86.

00 89.

Y

600 98.

81.

84.

Y

do 87.

Y

93.

96.

H3=0o0> 99.

WO 99/06397 PCTUS98/1 5479 00 100.

103.

H3=CO 106.

00 109.

0 0 112: -343- Table 3B cont.

R

101.

104.

H

3 C0T 00 107.

110.

0 0 113.

0A0 0 0 102.

F3O 105.

F3

N~

0.

00 114.

P

3 1 00 115. 116.

117.

WO "9/06397 PCTIUS98/1 5479 118.

F3 121.

124.

124.

-344- Table 3B cont.

R

119.

y 122.

120.

123.

126. 125.

y 127. 129.

128.

130. 131.

132.

WO 99/06397 WO 9906397PCTIUS98/I 5479 133.

NV

136.

139.

qF 3

V

142.

ooc v -345- Table 3B cont.

R

Hy 134.

9F 3 )y 137.

9F 3

Y

1 140.

HI-e 135.

138.

9F 3 Kr 141.

143. 144.

y %Ncft-"rA 147.

145. 146.

WO 99/06397 WO 9906397PCT/US98/15479 00 00 00 -346-

R

v 148.

oa,* 151.

154.

y 157.

160.

Table 3B cont.

R

y 149.

y C V FVro 15.

R

any 150.

153.

156.

159.

162.

161.

WO 99/06397 WO 9906397PCT/US98/1 5479 -347- Table 3B cont.

R

y 164.

0 165.

163.

166.

167.

y 170.

169.

168.

171.

xi~ 174.

K

172.

173.

175. 176. 17 177.

WO 99/06397 PCT/US98/15479 -348- Table 3B cont.

R

N7.

179.

178.

180.

183.

182.

181.

184.

0 185.

188.

188.

186.

FXY

187.

NC190.a 190.

189.

N

191.

192.

WO 99/06397 WO 9906397PCTIUJS98/15479 -349- Table 3B cont.

N

_y

N

193.

194. 195.

196.

197. 198.

199.

200.

201.

202.

203.

204.

205. 206. 27 207.

WO 99/06397 PCT/US98/15479 N 0 208.

y 211.

V

214.

K217.

217.

W.oN 0 -350- Table 3B cont.

R

209.

)y 212.

215.

ly 218.

221.

210.

213.

216.

y

KOV

219.

V

220.

222.

WO "9/06397 PCTIUS98I 5479 223.

y -351- Table 3B cont.

R

224.

y

N

226.

227.

N r 225.

228.

231.

234.

229.

232.

V

230.

233.

235.

236. 237.

WO 99/06397 PCT/US98/15479 -352- Table 3B cont.

R

N-

239.

242.

R

240.

240.

238.

241.

243.

syv

YV

244 0 244. 245.

246.

o 249.

247. 248.

250.

250.

252. 252.

WO 99/06397 PCT/US98/15479 -353- Table 3B cont.

R

254.

253.

255.

256.

257.

259.

262.

265.

260.

258.

y 261.

264.

267.

263.

266.

WO 99/06397 WO 9906397PCT/US98/15479 -354- Table 3B cont.

R

y 268.

270. 269.

271.

272.

274.

277.

280.

275.

273.

V

276.

V

279.

282.

278.

y 281.

WO 99/06397 PCT/US98/15479 -355- Table 3B cont.

R

283.

286.

y

N

289.

V

292.

295.

284.

Ny 287.

290.

293.

296.

296.

N

285.

288.

291.

294.

297.

297.

WO 99/06397 PCT/US9811 5479 -356- Table 3B cont.

R

298.

301.

304.

0, C 307.

310.

299.

KXcN 302.

y 305.

V

300.

303.

'IX Ny 306.

309.

312.

308.

311.

WO 99/06397 PCT/US98/15479 -357- Table 3B cont.

R

1< 313.

316.

314. 315.

317. 318.

319. 320.

321.

v 322. 323.

324.

325.

327.

326.

WO 99/06397 PCT/US98/15479 -358-

R

328.

331.

334.

Table 3B cont.

R

329.

332.

R

330.

335.

COOEt 336.

NO,

339.

V

N0 2 342.

337.

No0 2 340.

338.

341.

WO 99/06397 PCT/US98/15479 -359- Table 3B cont.

R

343.

346.

349.

0 352.

355.

SCN

344.

347.

350.

0 353.

356.

(>N

345.

K

1 348.

0 351.

0 354.

0 357.

WO 99/06397 PCTIUS98I1 5479 -360- Table 3B cont.

R

Y

7 v 358.

y 361.

$cVV0 364.

367.

359.

V

362.

0 365.

y 368.

Mo~O) 0 371.

y 360.

363.

366.

K

369.

V

370.

372.

WO 99/06397 PCTIUS98/1 5479 373.

0 376.

r 0 379.

0 382.

-361- Table 3B cont.

R

0 374.

MoO 0 377.

MoO 0 383.

Moo 0 386.

m0 M: 38 0 378.

381.

m~oa 0 384.

375.

0 387.

385.

390.

388. 389.

WVO 99/06397 PCT/US98/ 5479 -362- Table 3B cont.-

R

0 392.

y 0 391.

0 393.

394.

395.

396.

397.

398.

0 400.

CI~4 0 401.

399.

402.

403.

404.

405.

F

0 0 406. 407.

408.

WO 99/06397 PCT/US98/15479 -363- Table 3B cont.

R

0 410.

r

XCA

0 409.

0 412.

0 415.

411.

413.

414.

0 417.

416.

418.

419.

0 421.

OM. 0 424.

420.

OM. 0 423.

425.

426.

WO 99/06397 PCT/US98/15479 -364- Table 3B cont.

R

OMe 428.

omi 0 427.

0MG 0 430.

431.

0Me 0 429.

MOJIii~~ 0Me 0 432.

OMO 0 435.

OM. 0 433.

434.

MOO

Ohio 0 436.

437.

438.

moo 1Nrv 439.

tooI 440.

443.

441.

Me 442.

444.

WO 99/06397 PCr/US98/ 5479 8"0~;0 445.

13 KNrA 448.

Ny 451.

y 454.

N0 -365- Table 3B cont.

R

y

BSCYA

446.

8~00 449.

452.

455.

NJ

,I,

447.

450.

453.

456.

Ny"~ XrYo 457. 458.

459.

WO 99/06397 WO 9906397PCT/US98/15479 366- Table 3B cont.

R

460.

463.

461.

464.

467.

462.

465.

468.

B '11 466.

469.

470.

F c 473.

471.

474.

472.

WO 99/06397 PCT/US98/15479 475.

478.

481.

484.

F Y C3 ~r# o -367- Table 3B cont.

R

By 476.

479.

v 482.

477.

1

A

480.

483.

Fy 486.

F'>

489.

485.

487.

488.

WO 99/06397 PCT/US98/15479 -368-

R

490.

0 493.

0 o 496.

0 499.

502.

505.

Table 3B cont.

R

0 491.

o 0 494.

0 497.

0 500.

R

492.

^J4 0 495.

V

0 498.

0 o 501.

0 504.

507.

507.

503.

506.

WO 99/06397 PCT/US981 5479 -369- 00 00 00

CI

R

y 508.

511.

514.

517.

520.

Table 38 cont.

R

509.

512.

515, 518.

521.

R

510.

513.

y 516.

V

519.

522.

WO 99/06397 PCT/US98/15479 -370- Table 3B cont.

R

H

523.

526.

525.

525.

524.

527.

530.

528.

H

531.

529.

H

I-~

532.

535.

533.

534.

HJ

536.

537.

WO 99/06397 PCT/US98/1 5479 o538.

538.

-371- Table 3B cont.

R

J00o') 0

H

539.

0 542.

545.

r H548.

548.

H

540.

541.

543.

544.

H

546.

Joo') 0 549.

552.

547.

Ci "e =r~ 550. 551.

WO 99/06397 PCTIS98/1 5479 y 553.

alt556 556.

-372- Table 3B cont.

R

r 554.

V

557.

555.

558.

559.

560.

561.

Nc 564.

562.

0 563.

565. 566.

567.

WO 99/06397 WO 9906397PCTIUS98/15479 -373- Table 3B cont.

R

568.

571.

569.

570.

572.

573.

574.

575.

576.

KIcKrg0 579.

577.

578.

580. 581. 52 582.

WO 99/06397 WO 9906397PCTIUS98/15479 -374.

Table 3B cont.

R

583.

586.

V

584.

585.

587. 588.

589. 590.

591.

593.

594.

592.

596. 57 597.

595.

WO 99/06397 PCTIUS98/15479 00 -375- Table 3B cant.

R R R 00 0,> FO F~o FVO 8599. 600.

00 598.

K V~ FV

FF

601. 602. 603.

FV F 604. 605. 606.

606.

607. 608. 609.

1 610.F a 611. 612.

WO 99/06397 PCT/US98/I 5479

R

0 613.

H 616.

Nt0 H 0 619.

-376- Table 3B cont.

R

614.

H

MQ

617.

620.

R

615.

0 618.

621.

622.

V

0 623.

V

0 624.

00 625. 626.

627.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -377- Table 3B cont.

R

0 0 630.

628. 629.

00 631.

0 0 632.

Examale 340 trans. trans-4-( 1 3-Benzodioxol-5-Vl.2-(4-methoxvohel l1-(N-(3-methylbut- 1 -yf- N-ohenyl~aminocarbnlmethyI)-D2yrroidile-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I 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, 1H), 6.86 (dd, J=9 Hz, 1H), 6.89-7.00 (in, 21H), 6.97 J=1 Hz, 1IH), 7.04 J=9 Hz, 2H), 7.37 J=9 Hz. 2H), 7.40-7.47 (mn, 3H). MS mle C (53.12, 53.11), H (4.63, 4.80), N (3.33, 3.28).

WO 99/06397 PCT/US98/15479 00 -378- Example 341 trans. trans-4-(1 .3-Benzodioxol-5-yfl.2-(4-methoxyphelyl)-1-(Nbutyl.N-(4-methylpylamflocarboflylmethyfl-Dyrrolidifle- 3 00 sUsing the procedures described in Example 1, the title compound was prepared. 1 H NMVR (300 MHz, CD3OD) 8 0.87 (t1, J=7 Hz, 3H1), 1.20- 1.47 (in, 2.37 3H1). 2.83 J=7 Hz, 3.06-3.25 (in, 2H), 3.40- 00 3.50 (in, 1 3.51-3.63 (mn, 3H), 3.80 3.87 J=9 Hz, I1H), 5.92 2H), 6.74 J=8 Hz, 1 6.80-6.86 (in, 6.89 J=8 Hz, 21-), 7.04 J=2 Hz, 1 7.12 J=8 Hz, 2H), 7.19 -3=8 Hz, 2H1). MS (DCI) mle 545 Analysis calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.20; H, 6.81; N, 5.03.

is trans. trans-4 -(1-33 Ben zod io xo 1-5-yi)-2 rogo0xyph enl)1 di(n-butyflamino~carboflyfliethyl)-pyrroliding-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.30 (2H, d, 7.03 (1 H, d, 6.83 in), 6.72 (1 H. d, 5.95 (1 H, d, 5.93 (1 H, d, J=2), 3.88 t, 3.73 d, J=12), 3.58 mn), 3.53-3.20 in), 3.10-2.90 in), 2.72 d, J=15), 1.79 (2H, q, 1.50-1.05 (8H, in), 1.02 (3H, t, 0.87 t, 0.80 (3H, t, MS (DCI/NH3) m/e 539 Anal calcd for C31 H42N206 0.5H-20: C, 67.98; H ,7.9 1; N, 5.11. Found: C,68.24; H, 7.70; N, 5.03.

Example 343 trans, trans4- (1.3 Be oi oy hnl-1-N -in butyflaminocarbolylnethyflDyrrolidine3-carboxyuic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.31(2H, d, 7.13 (2H1, d, J=9).

7.03 (1 H, d, 6.84 (1 H, dd, J=6, 6.73 (1 H, d, 5.95 (1 H, d, 5.93 d, 3.76 (11H, d. J=10), 3.60 (1H, in), 3.55-3.20 (4H-, in), 3.13-2.88 (41, in), 2.75 (1H, d, J=15), 2.55 (2H, t, J=B),1.62 (2H, q, 1.50-1.00 (81H, in), 0.92 t, 0.85 t, 0.78 t.

MS (DCI/NH3) mle 523 Anal calcd for 031 H42N2O5-0.25 C. 70.63; H, 8.13; N, 5.31. Found: C, 70.55; H, 8.08; N, 5.18.

WO 99/06397 PCT/US98/15479 00 -379- Example 44 trans- trans- Metho xyh enyl) .3-be nzo dio xol-5-yl)- 14-3- (N- 12rO 1yl -N -r.D1entane sulf onyl amino) pro pyllpyrrol idi ne-3- carboxy i c acid 00 5 Using the procedures described in Example 316, the title compound was prepared. 1 HNMIR (300MHz, CDCI3) 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 00 (mn, 4H), 2.05-2.15 (mn, 1H), 2.43-2.56 (in, 1H), 2.72-3.1 (in, 7H), 3.27- 3.4 (in, 2H), 3.5-3.6 (in, 2H), 3.80 3H), 5.95 2H), 6.73 J=BHz, Ni 10 1H), 6.8-6.9 (mn, 1H), 6. 85 J= 9Hz, 2H), 7.02 J=2Hz, 1H), 7.80 (d, J=9Hz, 2H).

trans, trans-4-(1 .2-Di hyd robenzof uran-5-yfl-2-(4-gthylphenyfl)-1 (N.N-di(n-butyflaminocarbnylnethfl-pyrrolidile-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDC13 8 7.40 (3H, in), 7.22 (2H, d, J=8), 7.13 (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, in), 3.20 (2H, t, 3.15 (1 H, in), 3.10-2.90 (2H, in), 2.63 (2H, q, 1.47 (2H, in), 1.31 (4H, in), 1.12 (3H, t, 1.10 (2H,in), 0.92 (3H, t, 0.80 (3H, t, MS (DCI/NH3) in/e 507 Anal calcd for C31H42N204 TFA: 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 .3-Benzodioxol-5-yfl-2-(4-nethoxyphenyl)- I pe ntyflN- phenyl ainno carbofyl) m ethyl1yrrol idi e3-crboxyli c 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, 3H), 1.33 (in, 4H), 2.72 J=15.2 Hz, 1H), 2.81 (in, 1H), 3.1-1-3.2 (mn, 2H), 3.45-3.57 (in, 2H), 3.79 3H), 3.83 J=9.8 Hz, I1H), 4.54 (in, 1 5.92 2H), 6.73 .J=7.8 Hz, 1 6.83 (in, 3H), 6.98 (bs, 2H), 7.04 J=1.7 Hz, 1 7.07 7.37 (in, 3H). MS (DCI) mle 545 Anal calcd for C32H33N206 0.35H20: C, 69.76; H, 6.71; N, 5.08. Found: C, 69.72; H, 6.66; N, 4.94.

WO 99/06397 PCT/US98/15479 00 -380trans. trans-4-(1 Ben zodi oxol -5-yI)-2 met hoxyph efyfl- 1 buy)N(-rfurmty12ey~mn~abnlmty)2roiie 2-carboxylic -acid 0 5 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, 1H), 3.10 J=9.5 Hz, 00 1H), 3.21-3.27 (mn, 1IH), 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, 3H1), 7.33 J=7.5 Hz, 1H), 7.40 1H), 7.58 J=7.8'Hz, 1H), 7.69 Hz, 1H1). MS (DCI) m/e 599 Anal calcd for C32H33F3N206:

C,

64.21; H, 5.56; N, 4.68. Found: 0, 64.09; H, 5.63; N, 4.57.

trans. trans-4-(1I.3-Benzodioxol-5-yfl-2-(4-nethoxyphenyl)-l-(Nprogyl-N-(4morhoinylcarbny)aminocarbonylinethyl)-Pyrrolidine- 3 carboxyigId Using the procedures described in Example 1. the title compound was prepared. 1 H NMR (300 MHz, CD3OD) S 0.78 J=7 Hz, 3H), 1.43 (q, J=7 Hz, 2H), 2.07-3.01 (in, 1K), 2.76 (dd, J=7, 9 Hz, 2H), 2.77-3.00 (in, 3.05 (3.70, J=m Hz, 11 3.76 3H), 5.88 2H), 6.67 J=8 Hz, 1H), 6.80 (dd, J=7 Hz, 1H), 6.83-6.90 (in, 2H), 6.98 J=2 Hz, 1H), 7.32- 7.39 (in, 2H). MS m/e calc'd for C29H39N307: 540.2710,.

Found 540.2713.

ExamI2le 349 trans, trans-4-(1 .3 Ben zodioxol-5-yfl-2 metho xyphe nyl)- (cis- 2 .6-dimethylligeridin-1 -y)carbonylmethylb-yrrolidine-3-carboxylic aidi Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 0.94 J=7 Hz, 3H), 1.15d 3H), 1.10-1.70 (in, 6H), 1.70-1.90 (mn, 1H), 2.9. J=13 Hz, 1H), 3.00-3.20 (in, 2H), 3.50 (3.70, J=m Hz, 2H), 3.79 3H), 3.80-4.00 (in, 1H), 4.10-4.65 (mn, 2H), 5.95 2H), 6.70 (7.10, J=m Hz, 5H), 7.35 (in, 2H). MS m/e calc'd for C28H35N206: 495.2495. Found 495.2493.

WO 99/06397 WO 9906397PCTIUS98I1 5479 -381- 00 00 1- I0 trans, trans-2-(4-Methoxymethoxyphelyfl-4-(1 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 57-59 0 C. 1H NMR (CDCI3, 300 MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.28-1.36 (in, 4H), 1.93 (sextet, J=7Hz, 2H), 1.72 J=7Hz, 2H), 2.20-2.32 (in, 1H), 2.72-3.10 (in, 7H), 3.18-3.41 (in, 2H), 3.43 (dd, J--aHz, J=9Hz, 1H), 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=8Hz, 1H), 6.98-7.02 (in, 3H), 7.32 J=9Hz, 2H). MS (DCI/NH3) m/e 591 is Examp trans. trans-4-(1 .3-Benzodioxol-5-yl)-2-(4-nethoxylhenl)f-l butyfl)N-gpenylamiflo~carbonylinethylpyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 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 (in, 2H), 3.37-3.49 (in, 3.70 3H), 3.80 (d, J=9.8 Hz, 1 4.53 (in, 1 5.83 (in, 2H), 6.65 J=8.1 Hz, 1 6.72 6.76, J=in Hz, 3H), 6.87 (mn, 2H), 6.95 J=1.7 Hz, 1H), 7.03 (in, 2H), 7.29 (in, 3H). MS (DCI) Wne 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.

Example 352 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-inethoxyphenYl)-l grpl--hnlmn~abnlmehlproiie3croyi acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.99 J=6.8 Hz, 6H), 2.71 J=1 5.6 Hz, 1 2.84 (mn, 1 3.13-3.18 (in, 2H), 3.45-3.58 (in, 2H), 3.79 3H), 3.88 J=9.8 Hz, 1H), 4.80 (in, 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 (in, 3H). MS (DCI) m/e 517 Anal calcd for WO "/06397 PCT/US98/15479 00 c-I -382- S C30H32N206 .4H20 -0.08CH3C02C2H5: C, 68.65; H, 6.28; N. 5.28.

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

00Exml35 trans. trans-4-(4-Propoxypheflyl)2-(4-methoxylhenfl)l- -(N.N-di(nbutyflaminocarbonylmethyl)-Dyrrolidile--carboxylic acd N- Using the procedures described in Example 1, the title compound 00 was prepared. I H (300MHz, CDCI3 8 7.42 (2H1, d, J=lOHz), 7.38 (2H, d, cIJ=lOHz), 6.92 d, J=lOHz), 6.88 d, J=lOHz), 5.13 bd, J=l2Hz), 4.02 in), 3.90 t, J=BHz), 3.80 (3H1, 3.71 (3H1, mn), 3.40 (2H, in), 3.19 (1H, in), 3.10-2.90 in), 1.80 (2H, in), 1.48 (2H, in), 1.29 (4H, in), 1.13 in), 1.03 t, J=8Hz), 0.92 (3H, t, J=9Hz), 0.82 t, J=9Hz). MS (DCI/NH3) mWe 525 Anal calcd for C31H44N2O5- 1 TFA: C, 62.06 H 7.10; N, 4.39 Found: C, 62.43; H, 7.28; N, 4.39.

Examlle 354 trans, trans-4-( 1.3-Benzodioxol-5-yfl.2-(4-mlethoxynheflYl)- .2.3.4-tetrahydroguinolin- 1 -yl)carbonyflrfethyOP1yrrolidifle- 3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.88 (quintet, J=6.5 Hz, 2H-), 2.67 J=6.4 Hz, 2H), 2.87 J=8.6 Hz, 1 3.14 (in, 2H), 3.42 (dd, J=4.6, 9.7 Hz, 1 3.53-3.70 (in, 3H), 3.72-3.78 (in, 1 3.77 3H), 3.86 J=9.6 Hz, I1H), 5.91 2H), 6.73 J=8.1 Hz, I1H), 6.83 (in, 3H), 6.98 J=1.1 Hz, 1H), 7.02-7.23 (in, 6H). MVS (DCI) m/e 515 Anal calcd for C30H3ON206 -0.3H20 0.15 CH3CO2C2H5: C, 68.93; H, 6.01; N, 5.25. Found: C, 68.91; H, 5.86; N, 5.19.

Eall trans.t rans2(3.4-Diiethgxyhenl4-( 1.3-enzodioxgl-5-yfl-l (NNd~-uy~mncroymthl-2roiie3croyi acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 64-65 OC. 1 NMR (CDC13, 300MHz) 8 0.79 J=7Hz, 3H), 0.88 J=7Hz, 3H),1.07 (sextet, .I=7H7; 2H). 1.20-1.35 (in, 4H), 1.43 (sextet, J=7Hz, 2H), 2.83 (d, WO 99/06397 PCTIUS98/15479 00 -383- J=1 3.5Hz, I1H), 2.94-3.17 (in, 4H), 3.22-3.42 (in, -1 3.40-3.48 (in, 3H), 3.58-3.65 (in, 1H), 3.82 3H), 3.85 4H),5.92 2H), 6.73 J=8Hz, 1H), 6.81 J=8Hz, 1H), 6.86-6.96 (in, 3H), 7.07 J=3Hz, 1H). MS (DCI/NH3) m/e 541 00 trans, tra ns-2 Dim ethoxyh e nyfl-4- (1I.3- ben zod Ioxol I -2- 00 NI 0 Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 75-86 OC. 1 HNMR (CD300, 300 MHz) 5 0.75 J=7Hz, 3H), 0.82 J=7Hz, 3H), 1.32-1.43 (mn, 6H), 1.65-1.77 (mn, 2H), 3.0-3.09 (in, 4H), 3.23-3.27 (in, 2H), 3.44 (t, J=6Hz, 1H), 3.47-3.56 (in, 2H), 3.78 J=9Hz, 11H), 3.83-3.93 (in, 2H), Is 3.87 3H), 3.92 3H), 4.63 J=l3Hz, 1H), 5.97 2H), 6.82 (d, J=7Hz, 1H), 6.93 J=7Hz, 1H), 7.06 J=7Hz, 1H), 7.08 J=3Hz, 1H), 7.16 (dd, J=3Hz, J=7Hz, 1H), 7.27 J=3Hz, 1H). MS (DCI/NH3) W/e 591 Eample 357 trans, trans-2-(3.4-Dimethoxypheflyl)-4-( 1.3-benzodioxol-5-yl)-I -12- Using the procedures described In Example 1, the title compound was prepared and isolated as a white solid. in.p. 65-66 OC. 1 H NMR (CDC13, 300 MHz) 8 0.80 J=7Hz, 3H), 0.89 J=7Hz, 3H), 1.23-1.48 (mn, 6H), 1.43 (sextet, J=7Hz, 2H), 1.72 (sextet,J=7Hz, 2H), 2.25-2.35 (in, 1H), 2.73-3.10 (in, 7H), 3.19-3.32 (mi, 2H), 3.45 (dd, J=3Hz,, J=9Hz, 1H), 3.53-3.59 (mn, 1H), 3.68 J=9Hz, 1H),3.87 6H), 5.95 2H), 6.74 (d, J=8Hz, 1H), 6.79-6.86 (mn, 2H), 6.92-6.97 (mn, 2H), 7.02 1H). MS (DCI/NH3) Wie 605 WO 99/06397 PCT/US98/15479 00 c-I -384trans. trans-2-(4-Methoxyphenfl)f 4 1.3-benzodioxol-5-yfl- 12- (Dhalimido~ethyll.pyrrolidlfe3-carboxylic- acid 00 The compound of Example 1C (250 mg), N-bromoethylphthalimlde (206 mg), and diisopropylethylamifle (175 mg) were dissolved in 1 mL of acetonitrile and heated for 2.5 hours at 95 OC. Toluene was added, and the mixture was washed with KHCO3 solution. The solution was 00 dried (Na2SO4) 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 of Example 1 D to give 130 mg of the title compound as a white powder.

1 H NMR (300 MHz, CDCI3) 8 3.12-3.26 (in, 2H), 3.60-3.75 (in, 2H), 3.70 3H), 3.98-4.12 (in, 2H), 4.45-4.55 (mn, 1H), 4.69 J=9Hz, 1H), 4.76- 4.88 (mn, 1H), 5.96 2H), 6.55 J=8Hz, 6.60-6.70 (mn, 3H), 6.79 J=8Hz, 1H), 7.05-7.45 (in, 5H), 7.75 J=7Hz, 1H).

trans. trans-74-(l .3Benzodioxol5vl)244iethoxynhenyl)-I 12ny)Npe-lmn~abnl~mtv~~roiie3croyi acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 5 0.86-0.98 (in, 6H), 1. 17-1.22 (in, 1H), 1.23-1.41 (in, 3H), 2.70 (dd, J=11.2, 15.3 Hz, 1H), 2.83 (in, IH), 3.10-3.21 (in, 2H), 3.45-3.60 (in, 2H), 3.79 3H), 3.86 (in, 1H), 4.74 (in, 1H), 5.91 (in, 2H), 6.73 (dd, J=1.1, 7.7 Hz, 3H), 6.82 (in, 2H), 7.04- 7.14 (in, 3H), 7.36 (in, 3H). MS (DCI) in/e 545 Anal calcd for C32H36N206 0.25 CH3C02C2H5: C, 69.95; H, 6.76; N, 4.94. Found:

C,

70.03; H, 6.54; N, 4.78.

Examp~le 360 -trans, trans-4-( 1 3 Benzodioxol-5-y-2(4-methoxyphenyl1 butyl-N-(2-na hthyfl ami noca rbonl miethyl) -gyrrol idin e3carboxlic acid Using the procedures described in Example 1, the title compound was prepared. I NMR (300 MHz, CD3Q1D) 8 0.53 J=7 Hz, 3H), 1.23- 1.39 (mn, 4H), 1.40-1.55 (mn, 3H), 2.60-2.72 (in, 2H), 3.00-3.80 (in, 3.66 3H), 5.87 2H), 6.39 J=9 Hz, 2H), 6.74-6.85 (in, 3H), 7.17 WO 99/06397 PCT/US98/15479 0O9/697PTU98I57 -385- J=2 Hz, I1H), 7.40 (dd, J=8 Hz, I1H), 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.

00 ~a~e~ trans. trans-2-( 4-P ropoxyohenyl)-4-(1 .3-benzodioxol-5-Yfl-l -r2-(NpropyI-N-rn-pentanesulfonylamino~ethvl1yrroidineacarboxylic acid 00 Using the procedures described in Example 66, the title compound 0 was prepared and isolated as a white solid. m.p. 53-54 0 C. 1 NMR (CDC13, 300MHz) 0.79 J=7Hz, 3H), 0.89 J=-7Hz, 3H), 1.03 (t, J=7Hz, 3H), 1.24-1.34 (in, 4H), 1.43 (sextet, J=7Hz, 2H1), 1.67-1.75 (in, 2H), 1.80 (sextet, 2H1), 2.23-2.33 (in, 1H), 2.72-2.93 (in, 5H), 3.05 (septet, J=7Hz, 2H), 3.15-3.35 (in, 2H), 3.42 J=9Hz, 1H), 3.54-3.62 (in, 1H), 3.67 J=9Hz, 1H), 4.90 J=7Hz, 2H1), 5.95 2H1), 6.73 (d, J=BHz, 1H), 6.85 J=8Hz, 2H), 7.02 1H), 7.32 J=8Hz, 2H). MS (DCI/NH3) m/e 589 Examn~le 36 !0 -trans, trans- 4 .3.Benzodioxol5yf-2(4-methoxynhenyl"l methylindolifl-1 -yflcarbonyflnmethybOnvrrolidie3-Carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 mixture of indole C2 diastereoinerS, 0.95 (in, 1.5 (CH3 1.05 6.3H, 1.5 2.62 (in, 1KH), 3.01 (in, 2K), 3.14-3.25 (in, 1KH), 3.37-3.52 (in, 1.5K), 3.56-3.80 (in, 2H), 3.65 1.5 (CK3O)), 3.76 1.5 (CK3O)), 3.93 (in, 0.5K), 4.05-4.13 (in, 4.42 (in, 0.5H), 4.65-4.74 (in, 1K), 5.91 (in, 2K), 6.72 J=8.1 Hz, 0.511), 6.75 (in, 6.85 (in, 2K), 6.92 J=8.5 Hz, 1H), 7.00-7.06 (in, 2H), 7.14 J=7.7 Hz, I1K), 7.21 J=6.6 Hz, 1KH), 7.38 (in, 2K), 7.99 (in, 1H). MS (DCI) Wne 515 Anal calcd for C30H30N206 0.35H20 0.3 CH3CO2C2H5: C, 68.47; H, 6.10; N, 5.12. Found: C, 68.46; H, 5.97; N, 5.07.

WO 99/06397 PCT/US98/15479 00 -386trans. trans-4-(1 .3-Benzodioxol.5-yfl-2-(4-methoky~hel)- 1 hyd roxy-3-p ropyIhex- 1 -yl .Doyrroli dine-3-carboxylic acid Using the procedures described In Example 1, the title compound 0s was prepared. I H NMR (300 MHz, CD3OD) 8 1.06 (in, 6H), 1.26-1.60 (mn, 9H), 3.16 (dd, J=1 0.9, 12.6 Hz, 1 3.18 J=1 1 Hz, 1 3.44 Hz, I1H), 3.61 J=1I1 Hz, I1H), 3.73 J= 11.0 Hz, 1 3.85 (in, I H), 00 3.96-4.17 (mn, 2H1), 4.02 1.5 (CH3O diastereomer)), 4.03 1.5 (CH3O diastereoiner)), 6.15 2H), 7.01 J=8.1 Hz, 7.00 J=8.1 Hz, to0.51-), 7.10 (mn, 1H), 7.23 (mn, 3H), 7.77 (in, 2H). MSf (DCI.) Wne 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.

is trans. trans-4- (1 Ben zodi oxoI-5-yfl-2-(4-neth oxylh enl)-I h eotyfl)-N .4-di methoxybelzyl) aIfnfo)ca rbonl)l methy) 1y rro Idi ne- 3 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR ('300 MHz,*CD3OD) 81:1 mixture of rotamers, 0.61 J=7.1 Hz, 1.5H), 0.72 1.5H), 0.76 J=7.1, 1.5, 0.83, t, 7.3 Hz, 1.5H1), 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 1.5H1), 3.77 1.5H1), 3.78 3.79 3.86 J=9.8 Hz, 0.511), 4.19 (d, J=17.7 Hz, 4.29 J=15.2 Hz, 4.40-4.49 (mn, 0.5H),.4.47 (d, J=15.3 Hz, 0.5H), 4.60 J=17.6 Hz, 0.511), 5.93 (in, 2H), 6.46 (dd, J=1.7, 8.2 Hz, 0.511), 6.52 J=2.0 Hz, 0-511), 6.74 (mn, 2.5H1), 6.80 1H), 6.83- 6.88 (mn, 1H), 6.92 (in, 1.5H), 7.03 (dd, J=1.7, 6.8 Hz, 1H), 7.19 (in, 1H), 7.36 (mn, 1H). MS (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.

trans. trans-4-( 1.3Benzodioxol-5-l)-2-(4-methoxYlheny)-1 nd ol in- 1 -yl' garbonyhinmethyfl)yrrgli dine-3-carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 82.97 (dci, J=8.1, 9.5 Hz, 1 H), 3.10 J=8 .1 Hz, 2H), 3.16-3.22 (in, 2H), 3.51-3.68 (in, 3H), 3.73 (mn, WO "/06397 PCT/US99/15479 00 -387- 3H), 3.83-4.05 (in, 3H), 5.90-(in, 2H1), 6.73 J=8.1 Hz, 11H), 6.86 (in, 311), 6.99 (dt, J=1.1, 7.4 Hz, 1H), 7.08 J=0.7 Hz, 1H1), 7.11 (in, IIH), 7.18 J=7.1 Hz, 1H1), 7.38 J=8.5 Hz, 2H), 8.02 1H). MS m/e 501 Anal calcd for C29H128N206 0.5 H20 0.15 00 5 CH3CO2C2H5: C, 68.01; H, 5.82; N, 5.36. Found: C, 68.03; H, 5.65; N, 5.25.

00Exml36 trans. trans-4-(1 .3-Benzodioxol-5.yl)-2-(4-methoxyphenyl)-1 0 butyl-N-(2-chlorphenylainocarbonylnethyflDyrrolidile-3- Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD300) 50.89 (dt, J=7 Hz, 3H), 1.23- 1.51 (in, 4H1), 2.52-4.00 (in, 8H1), 3.78 J=6 Hz, 3H1), 5.92 J=6 Hz, 6.70-6.87 (in, 41H), 7.02-7.21 (mn, 4H1), 7.27-7.52 (in, 3H). MS (DCI) m/e 565 Analysis calcd for C311H32N206CI 0.61120: C, 64.66; H, 5.99; N, 4.86. Found: C, 64.59; H, 6.00; N, 4.64.

Example 36 trans, trans-2 -(4-Meth oxp he nyl)-4-(1 .3-ben zodioxol-5-yi)- I- (3.4.5-trimethoxybenzylflyrrolidine-3-carboxlic 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 dilsopropylethylamine 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 1 H NMR (300 MHz, CDCI3) 82.75 J=9Hz, 1 2.95-3.05 (in, 2H1), 3.20 J=11 Hz, 3.45-3.55 (in, 1H1), 3.7-3.8 (mn, 2H), 3.84 3H), 5.95 (dd, J=2Hz, 6Hz, 2H), 6.55 2H), 6.70 J=BHz, 1IH), 6.30-6.35 (in, 1H1), 6.90 J=9Hz, 2H), 7.13 J=2Hz, 11H), 7.43*(d, J=9Hz, 2H).

WO 99/06397 PCT/US98/15479 00 -388trans. trans-4-( 1.3- Ben zodo xol -5-yfl-2- (4-m eth oxyphe nyfl-I butyl- N- (3-ch loroph enyl) a minoca rboflylm ethyl) -pyrrolldi ne-3- 00 s" Using the procedures described In Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.89 J=7 Hz, 3H), 1.20- 1.42 (in, 4H), 3.42-3.87 (mn, 9H), 3.9 5.96 2H), 6.75 (7.10, J=in 00 Hz, 7H), 7.33-7.50 (in, 4H). MS mWe 565(M+H). Analysis calcd for

C

3 1H33N206C1.1.OCF3C00H: C, 58.37; H, 5.05; N, 4.13. Found: C, 58.41; H, 4.99; N, 4.08.

trans..trans-2-(4-Methoxphenyfl-4-(1 .3-benzodioxol-5-yli)-1 -r2-(di-ibutylamino)oyrimdin-4-yllyrrolidile-3-carboxylic acid is The compound resulting from Example 10 (0.25 g) was reacted with 0.11 g of 2,4-dichioropyriinidine and 0.175 g of diisopropylethylainine in 1 mL of acetonitrile for 2 hours at room temperature to give 0.218 g of ethyl 2-(4-inethoxphenyl)-4-(1 ,3benzodioxol-5-yl)-1 -(2-chloro-4-pyrimidyl)-pyrr olidifle-3carboxylate. This compound was reacted with 1 mL of dibutylamine in.

2 mL of toluene at 125 00C for 17 hours. The resulting ethyl este r was hydrolyzed by the method of Example 1D to give 0.142 g of the title comopund as a white powder. 1 HNMR (300 MHz, 0D013) 80.75-0.90 (broad, 6H), 1.1-1.3 (br, 4H), 1.35-1.55 (br, 4H), 3.05 (mn, 1H1), 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, 5.87 2H), 6.3 (br, 1H), 6.67 J=8Hz, 1H), 6.7-6.85 (in, 4H), 7.10 J=9Hz, 2H-).

trans. trans-4-(1 .3-Benzodioxol-5.yfl-2-(4-methoxylhelyl)-1 Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3OD) 8 0.90 J=7.5 Hz, 3H), 1. 12 3H), 1.14 3H), 2.06 J=7.5 Hz, 2H), 2.73 J=15.3 Hz, 1H), 2.91 J=9.5 Hz, 11H), 3.11 J=15.6 Hz, 1H), 3.21 J=8.8 Hz, 1H), 3.50- WO 99/06397 WO 9906397PCTAUS98/1 5479 389- 3.61 (in, 2H), 3.80 311), 4.00 J=10.2 Hz, 5.91 2H1), 6.74 (d, J=7.8 Hz, 1H1), 6.85 (in, 3H), 6.93 (mn, 1H), 6.98 (in, 1H), 7.03 J=1.7 Hz, 1H), 7.17 (in, 2H), 7.36 (mn, MS (DCI) Wne 545 Anal calcd for C32H36N206: C, 70.57; H, 6.66; N, 5.14. Found: C, 70.17; H, 6.53; N, 4.97. 00 00 5 Example371 trans, trans-2 Ethyl phenyl-4- 5-i ndanyl)~- 1 N -di(nbutyflaminocarbonylmethyl-yrrolidine-3-carbxylic acid 1 0 Using the procedures described in Example 1, the title compound was prepared. 1 H (300MHz, CDCI3) 8 7.25 (3H, mn), 7.21 (1 H, d, 3H1z), 7.17 (3H, mn), 3.80 (111, d, 10OHz), 3.65 (1H, ddd, 6, 5, 3Hz), 3.4 (4H, in), 3.10 (2H, in), 2.98 (2H, in), 2.88 (5H, in), 2.79 (1H1, d, 16Hz), 2.62 (2H, q, 7Hz), 2.05 (2H, mn), 1.42 in), 1.32 (1 H, mn), 1.21 (3H, t, 7Hz), Is 1.05 (211, sext, 7Hz), 0.87 (3H, t, 7Hz), 0.79 (3H, t, 7Hz). MS (DCI, NH3) mWe 505 Anal calcd for C32H44N203: C, 76.15; H, 8.79: N 5.55.

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

Examlp 32 trans. rans-2-(3.4-Difluoroo~henyll-4-(1 .3-benzodioxol-5-yfl)-1-(N.Ndi(n-butylaminocarbonylnethyl-yrrolidie-3-carboxylc 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 NMR (CDC13, 300 MHz), 8 0.83 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.13 (sextet, J=7Hz, 2H),1.20-1.32 1.36-1.49 2.85-2.93 2.98-3.23 (mn, 4H), 3.36-3.45 (in, 3H), 3.58-3.66 (mn 1H), 3.94 (d, J=8Hz, 1H), 5.93 2H), 6.72 J=7.5Hz, 1H1), 6.84 (dd, J=lHz, 1H), 6.98 J=7.5Hz, 1H), 7.08-7.15 (in, 2H), 7.22-7.28 (mn, 1H). MS (CDI/NH3) m/e517 Examle37 tran,trans-2-(3.4-,Dif luoroDhelyll-4-(1 .3-be nzodioxol-5-yl)- 1 -r2-(Npropyl-N-rn-pentanesulfonylaminon~ethyIlyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. 71-72 OC. I 1 H NMR (CDC13, 300 MHz) 8 0.82 J=7Hz, 3H1), 0.90 J=7Hz, 3H), 1.25-1.38 WO 99/06397 PCTIUS98/15479 00 c-i -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 (mn, 5H), 2.98-3.12 (in, 2H), 3.15-3.34 (in, 2H), 3.45 (dd, J=3Hz. J=9Hz, 1H), 3.53-3.60 (in, 1H), 3.71 J=9Hz, 1H), 5.96 (s, 2H), 6.75 J=9Hz, 11H), 3.82 J=2Hz, J=9Hz, 1H), 5.96 J=2Hz, 00 1H), 7.09-7.18 (in, 2H), 7.23-7.34 (mn, 1H). MS (CDI/NH3) m/e567 00 Exm 7 trans, trans-4-(1 Benzodioxol-5-yi)-2-(ethoxynethyfl)-1 -N-di(nc-ibutyflamlnocarbonylmethyl-yrrolidile-3-.-'arboxlc acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.53. 1 H NMR (CDCI3, 300 MHz, rotameric forms) 8 0.70 J=7Hz), 0.80 J=7Hz) and 0.96-1.04 (in, 6H total), 1.04-1.75 (in, 11H), 1.34-1.53 (br mn, 4H), 2.65 (AB) and 2.80-3.08 (in, 2H total), 3.10-3.82 (br m, 12H), 4.03 (in) and 4.22-4.45 (br mn, 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 C25H-38N206 -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-yfl-2-(rl-butyfl) 1 di(n-butyfaininocarbonylnthyl)Pyrrolidifle-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a colorless wax. TLC (10% MeOH-CH2CI2) Rf 0.37. 1 H NMR (CDC13, 300 MHz, rotameric forms) 6 0.71 J=7Hz) and 0.77-1.05 (in, 9H total), 1.05-1.20 (in, 2H1), 1.20-1.72 (br mn, 13H), 2.48-2.52 (in, 1H), 2.87-3.00 (mn, 11H), 3.05-3.60 (mn, 5H), 3.60-3.80 (br mn, 2H), 3.88-4.05 (br mn, 11H), 4.28 (br d, J=l5Hz, 1H total), 5.90 and 5.92 2H total), 6.67-6.82 (in, 3H total). MS (FAB) m/e 461 Anal calod for C26H40N205 1.75 H20: C, 63.45; H, 8.90; N, 5.69.

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

WO 99/06397 PC'T/US98/15479 00 -391trans, trans-4-(1 .3-Benzodioxol-5-yO)-2--(2-mlethylbutyfl-1 -(N.N-di(nbutyflaminocarbonylmethyl-yrrolidile-3-carboxylic acid Using the procedures described in Example 1, the title compound 00 was prepared and isolated as a colorless glass. TLC (10% MeOH- CH2CI2) Rf 0.49. 1 H NMR (CDCI3, 300 MHz, rotameric forms and mixture of diastereomers) S 0.69 (br t, J=7Hz) and 0.75-2.15 (several br 00 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), 6.67-6.90 (in, 3H total). MS (FAB) mle 475 trans, trans-4-(1 .3-Benzodioxol-5-yl)-2-(3-methylbUtyfl)1 -(N.N-dijrnbutyflaminocarbonylmethyl).Dyrrolidie- 3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. TLC (10% MeOH-CH2CI2) Rf 0.41. 1 H NMR (CDC13, 300 MHz, rotameric forms) 8 0.73 J=7Hz) and 0.77-1.05 (in, 12H total), 1.07-1.75 (mn, approx. 14H plus H20), 2.48-2.63 (in, 1H), 2.87-3.05 (in, 1H), 3.05-3.60 (several br m, 5H), 3.62-4.02 (br m, 2H), 4.29 (br d, D J=l5Hz, 5.89 and 5.93 2H total), 6.65-6.90 (in, 3H total). MS (FAB) mWe 475 trans.. trans- 2- (4-M ethoxyphenyfl-4-(1. 3-benzodioxol -5-yfl- 1 -f 2-(N- S3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 58-59 0 C. IH NMR (CDCI3, 300MHz) 8 0.78 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.27 (sextet, J=7Hz, 2H), 1.48 (mn, 4H), 2.22-2.30 (in, 1H), 2.62 3H), 2.68-2.78 (in, 1H), 2.84-3.03 (in, 5H), 3.08-3.31 (mn, 3H),3.39 (dd, J=3Hz, J=9Hz,1H), 3.50-3.58 (mn, 1H), 3.63 J=9Hz, 1H),3.79 3H), 5.95 2H), 3.73 (d, J=8Hz, 1IH), 6.83 (dd, J=2Hz, J=8Hz, 1H), 3.87 J=9Hz, 2H), 7.01 (d, J=2Hz, IH), 7.33 J=9Hz, MS (DCI/NH3) Wne 576 WO 99/06397 PCT/IJS98/15479 00 c-I -392c-Itrans, trans--24-DI(3.4difluorophefil)l I -(N.N-dl(nbutyflaminocarbgnylmethyl)-Oyrrolidile-3-carboxylic acid 00 Using the procedures described in Example 1, the title compound prepared. I H NMR (300MHz, CDC13 8 7.35 (2H, in), 7.18 (4H1, in), 4.87 (1H, d, J=12), 4.00-3.60 (5H, in), 3.60-3.10 (311, in), 3.10-2.90 (2H1, c-I im), 1.45 mn), 1.29 (4H, in), 1.15 (2H, in), 0.91 (3H, t, 0.83 (3H, 00 t, MS (DCIINH3) Wne 509 Anal calcd for C27H32F4N203- 0.75 TFA: C, 57.62; H, 5.56; N, 4.72. Found: C, 57.72; H, 5.67; N, 4.660.

0 Examgle 3Q trans, trans-4-(3.4-Dim ethyl 1helyl)-2-(4-iethoxylhenyl)- N-di(nbutyflamingcarbolylmethyl)-Dyrrolidine-acarboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 6 7.43 (2H1, d, 7.25 (1 H, bs), 7.18 (1H, dd, J=8, 7.11 (1H1, d, 6.90 (2H1, d, J=10), 5.48 (1H1, d, J=12), 4.26 (1H, d, J=18), 4.16 (2H1, in), 3.83 (2H, mn), 3.81 (3H, s), 3.56 (1H, bd, J=18), 3.37 (1H1, in), 3.20 (1H, mn), 2.96 (2H1, mn), 2.24 (3H1, 2.22 (3H, 1.47 (2H, in), 1.27 (4H, in), 1.10 (2H, in), 0.93 (3H, t.

!0 0.81 (3H, 11, MS (DCI/NH3) mle 495 Anal calcd for C3OH42N2O4- 1.25 TFA: C, 61.26; H, 6.84; N, 4.40. Found: C, 61.16; H, 7.05; N, 4.38.

Exampie 3AI trans. trans-2 .4.Di(3.f luorg-4-nethoxyghenl' 1 -(N.N-di(fltbutyl~aminocarboflY~Iiethyl-Dyrrolidine3carbgxylic 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 in), 6.93 (2H, in), 5.48 (1 H, in), 4.26 (1 H, in), 4.16 (2H, in), 3.83 (2H, mn), 3.87 3.56 (IH1, in), 3.37 (1H, mn), 3.20 (1H, in), 2.96 (2H, in), 1.47 (2H-, in), 1.27 (4H, in), 1.10 (2H, in), 0.93 (3H1, t. 0.81 (3H, t, MS (DCI/NH3) m/e 533 Anal calcd for C29H38F2N2O5- 0.75 H20: C, 63.78; H, 7,29; N, 5.13. Found: C, 63.77; H, 7.08; N, 4.99.

WO 99/06397 WO 9906397PCT/US98/I 5479 -393- 00 5 00 trans. trans-4 Ben zod ioxol 2-(4 -m eth oxylhe nyfl)-1 pentyfl. N-(3-methylphenyflamino~carbonyflmethyl~pyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.90 (in, 3H), 0.95 J=7.3 Hz, 3H), 1.13-1.37 (in, 4H), 2.30 3H), 2.34 (s (CH3 rotamer)), 2.73- 2.91 (in, 2H), 3.17-3.26 (in, 2H), 3.32-3.62 (in, 2H), 3.77-4.08 (mn, 1H), 3.80.(s, 3H), 4.71 (in, 1H), 5.92 (in, 2H), 6.61-6.84 (in, 6H), 7.04-7.16 (mn, 3H), 7.23-7.29 (in, 2H). MS (DCI) Wne 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-(l Ben zodi oxol- 5-yfl-2- (4-mneth oxyph enyfl)-1 butyl 1 naghthyflami noca ronylm ethyl) yrroldi ne-3-carboxyl ic Acd Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.40 (in, 1.40-1.60 (in, 2H), 2.42-2.80 (in, 2H), 2.85-4.00 (in, 6H), 3.77 J=1.5 Hz, 3H), 4.05-4.20 (in, 1H), 5.94 J=2 Hz, 2H), 6.6 (dd, J=9, 10 Hz, 1H), 6.70-6.85 (in, 4H), 6.95-7.02 (in, 2H), 7.17 (dd, 8H, 7.25 (dd, 8H, 7.38-7.60 (in, 4H), 7.87-8.00 (in, 2H). MS Wne 581. Analysis calcd for C35H36N206 1.4 H20: C.

26 69.38; H, 6.45; N, 4.62. Found: C, 69.36; H, 6.07; N, 4.41.

Example 34 trans. trans-2-(4-Methoxyphenyfl-4-(1 .3-benzodioxol-5-yfl-1 -r2-(Nphenyl-N-rn-hexanesulfonylamino)ethyllpyrrlidine-3-carboxylic acid Using the procedures described in Example 66, the title compound was prepared and isolated as a tan solid. in.p. 67-68 0 OC. I H NMR (CD3OD, 300 MHz) 8 0.88 J=7Hz, 3H), 1.25-1.40 (in, 6H), 1.73 (quintet, J=7Hz, 2H), 2.13-2.23 (mn, 1H), .2.64-2.88 (in, 3H), 3.02 (sextet.

J=8Hz, 2H), 3.44-3.53 (in, 2H), 3.58 J=9Hz, 1H), 3.56-3.75 (in, IH), 3.78 3H), 3.88-3.98 (mn, 1H), 5.93 2H), 6.72 J=9Hz, 1H), 5.78- WO 99/06397 WO 9906397PCTIUS98/15479 c-I -394- S 5.84 (in, 3H), 6.96 J=2Hz, 1KH), 7.20 J=9Hz, 2H), 7.27-7.36 (mn, N- MS (DCIINH3) m/e 609 trans. trans-4-(1 .3-Benzodioxol-5.yl2-(4.methoxvghenyl)- -12 m ethyl-i1 .2.3.4-tet-r-hydroguiflglifn-l1 -yflcarbony~methylD1Yrrolidifle- 3 0 Using the procedures described in Example 1, the title compound 0was prepared. 1 H NMR (300 MHz, CD3OD) 8 1.03 (in, 3H), 1.10-1.45 (in, 1KH), 2.10-2.85 (in, 4H), 2.90-4.00 (in, 7H), 3.76 (srl'.5H), 3.77 isomer), 5.90 (in, 2H), 6.70-7.40 (in, 11H). MS (DCI) m/e 529 Analysis calcd for C31 H32N206 -0.3 H20: C. 69.73; H, 6.15; N, 5.25.

Found: C, 69.74; H, 6.10; 5.01.

transg.trans- 4 .eflzodioxol-5-yl 2.(4-iethoxyghelyll b -utyl-heot-2-en-1 -ylyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 NMR (300 MHz, CD3OD) 6 0.86 J=7.0 Hz, 3H), 0.90 J=7.0 Hz. 3H), 1.20-1.41 (in, 8H), 1.95-2.06 (in, 4H), 3.24 J=11.0 Hz, 1H), 3.51-3.59 (in, 3H), 3.60-3.71 (in, 1H), 3.77-3.84 (in, 1H), 3.81 4.45 J=1 1.0 Hz, 1 5.52 J=7.4 Hz, 1 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 (mn, 2H).

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

EamJg-IE trans. trans23Fl uorO-4 mthg xyphenyI 4 ben zodio xol- 1 -f2-(N-po lNr!eansloyaioehyl~roiie3 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-65 OC. 1 H NMR (CDC13, 300MHz) 8 0.82 J=7Hz, 3H), 0.88 J=6Hz, 3H), 1.23-1.47 6H), 1.44 (sextet, J=7Hz, 2H), 1.71 (quintet, J=6Hz, 2H), 2.24-2.34 (in, 1H), 2.70-2.93 (mn, 5H), 2.96-3.12 (mn, 2H), 3.15-3.35 (mn, 2H), 3.43 (dd, .1-3R'A7. .I9Hz. 1H). 3.52-3.59 (mn, 3.66 (K J=9Hz, 1H), 3.87 3H), WO 99/06397 PCT/US98/15479 00 -395- S5.95 2H), 6.74 J=8Hz, I1H), 6.82 J=8Hz, I1H), 6.42 J=BHz, 1IH), 6.96 1H). 7.12 J=9Hz, 1H), 7.17 J=l2Hz, 1H). MS (DCI/NH3) mle 593 00' Example 388 trans, trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-methoxygheflyfl- 1 pyridyflmethvfloyrrolidine-3-carboxylic acid c-i Using the procedures described in Example 1, the title compound 00 was prepared. 1H NMR (300 MHz, CD3OD) 5 2.87 (in, 2H), 3.04 (dd, J=3.2, 9.7 Hz, 1 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, 1H), 6.79 (dd, J=1.7 Hz, 7.8H), 6.94 (in, 3H), 7.36-7.45 (in, 3H), 7.81 (in, 1H), 8.39 (in, 1H), 8.46 (dd, J=1.4 Hz, 1 Anal calcd for C25H24N205 0.70 H20 0.05 0H3C02C2H5: C, 67.34; H, 5.79; N, 6.23. Found: C, 67.31; H, 5.63; N, 5.90.

Examle38 trans, trans-! 2 (n-Hexyfl-4-(1 .3-benzodioxol-5-yfl- 1 -N-di~dbutyflaminocarbonylmethyl)-yrrolidine-3-carboxylic- acid Using the procedures described in Example 1, the title compound 0 was prepared. 1 H NMR (CDCI3, 300 MHz) 5 0.82-1.00 (in, 9H), 1.20-1.40 (in, 12H), 1.45-1.60 (in, 4H), 1.70-1.90 (br 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 (in, 2H), 4.14- 4.34 (in, 2H), 5.94 2H), 6.73 J=8.1 Hz, 1H), 6.79 (dd, J=8.1, 1.8 Hz, 1H), 6.87 J=1.8 Hz, IH). MS(DCI/NH3) Wne 489 Anal calcd for C28H44N205 -0.9 TEA: C, 60.53; H, 7.65; N, 4.74. Found: 0, 60.62; H, 7.69; N, 4.6 1.

Examle39 trans. trans-4-(1 .3-Benzodioxol.5-yfl-2-(4-inethoxyPheli)-l1 penlyl)-N-(4-f luoro-3methyl ph enyflami no) carbonyfl) nethyl) pyrro Iidifle- 3 carboxyl ic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD300) 8 0.92 (in, 3H), 0.97 J=7.1 Hz, 3H), .1.13-1.40 (in, 4H), 2.22 (in, 3H), 2.58-2.74 (mn, 1H), 2.78-2.87 3 5 (in, 1 3.09-3.25 (in, 2H), 3.39-3.60 (in, 2H), 3.70-3.90 (in, I1H), 3.80 3H), 4.70 (in, I1H), 5.93 (in, 2H), 6.70-6.76 (in, 1IH), 6.75 (dd, J=1.4, WO 99/06397 PCT/US98/15479 00 -396- 8.1 Hz, lH), 6.80-6.94 (in, 4H), 6.96-7.13 (in, 4H). MS (DCI.) m/e 577 Ni Anal calcd for C33H37FN206 0.25 H20: C, 68.20; H, 6.50; N, 4.82. Found: C, 68.21; H, 6.46; N, 4.74.

00 ExamplC 391 trans. trans-4-(1 3Bnoixl5y)2-4mtovhni- pyridyllmethylDYrrolidine-3-carboxylic acid 00 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.97 (dd, J=7.9, 9.7 Hz, 1 H), 3.04 J=9.6 Hz, 1IH), 3.18 (dd, J=4.4 Hz, 9.9H), 3.47 J=14.0 Hz, 1H), 3.59 (in, I1H), 3.78 3H), 3.96 J=9.9 Hz, 1H), 3.97 J=13.6 Hz, I1H), 5.90 (in, 2H), 6.73 J=8.1 Hz, 1H), 6.83 (dd, J=1.7, 7.9 Hz, 1H), 6.92 (in, 2H), 6.96 J=1.8 Hz, 1H), 7.28 (in, 1H), 7.44 (in, 2H), 7.53 J=8.1 Hz, 1 7.80 (dt, J=1.8. 7.7 Hz, 1 8.42 (in, 1 MS (DCI) mWe 433 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.

Exmpea tran. tans2-(3-Phenyllrop l 4 di(n-butflamiflocarbonlmlethyl-Dyrrolidin- 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 (in, 6H), 1.22-1.36 (in, 4H), 1.41-1.55 (in, 4H), 1.63-1.95 (in, 4H), 2.62 (dt, J=7.2, 2.1 Hz, 2H), 3.05-3.44 (in, 7H), 3.53-3.60 (mn, 2H), 3.65-3.76 (mn, 1H), 3.82-3.90 (mn, 1H), 3.96-4.10 (mn, 1H), 5.92 2H), 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 (in, MS(DCI/NH3) m/e 523 Anal calcd for C31H42N205 0.6 TFA: C, 65.43; H, 7.26; N, 4.74. Found: C, 65.28; H, 7.29; N, 4.50.

30Exmla9 -trp-ns-trans-2-(4-Methoxy-3luorophenyl)4(7methoxy- 3be nzodi oxol-5-yfl- 1 N -di(n-butyflarni nocrbonylm ethyl)pyrrolidin-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m-p. 115-117 0 C. IH NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.5 (in, WO 99/06397 PCT/US98/15479 00 -397- 8H), 2.85 J=l3Hz, 1H). 2.90-3.17 (in, 5H), 3.20-3.35 (in, 11H), 3.35ci 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, 0=Hz 1H), 7.05-7.20 (in, 2H).

ci trans -trans-2-(1 .4-Ben zgd 1oxan-6-yfl-4- (7-ineth oxy-l- .3-ben zod ioxol- 00 5-yfl-l -(N.N-di(n-butyflaminocarboflylmethyl)~-pyrrolidile- 3 carboxylic acid D Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. in.p. 107-110 OC. 1H NMR (300 MHz, CDCI3) 8 0.82 J=7Hz, 3H), 0.88 J=7Hz, 3H), 1.05-1.50 (in, 8H), 2.75 J=l3Hz, 1H), 2.90-3.12 (in, 4H), 3.32-3.60 (in, 5H), 3.69 J= 8Hz, 1 3.90 3H), 4.23 4H), 5.95 (dd, J=4Hz, 2Hz, 2H), 6.62 I1H), 6.70 I1H), 6.78-6.93 (m ,3H).

Example 395 trans, trans-4-(l.-ezdoo--l-2(-ehxoey) 1 butyl-2.fluoro-het-2-enl -yflyrrolidine-3-carboxylic acid 0 Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CD3QD) 8 0.84 J=7.0 Hz, 3H), 0.88 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, 1H), 3.32-3.42 (mn, 2H), 3.50 (in, 1 3.71 J=9.2 Hz, 1 3.78 3H), 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, 1H), 7.34 (mn, 2H). MS (DCI) mle 512 Anal calcd for C30H38FN05:

C,

70.43; H, 7.49; N, 2.74. Found: C, 70.58; H, 7.54; N, 2.66.

trans, trans-2-(3-Fluoro-4-ethoxy~henyl- 4 -(l.3-benzodigol- 5-yl)-l Using the procedures described in Example 66, the title compound was prepared and isolated as a while solid. m.p. 65-66 OC. I 1 H NMR (CDCI3, 300 MHz) 8 0.82 J=7Hz, 3H), 0.90 J=7Hz, 3H), 1.26-1.36 (mn, 4H), 1.41-1-52 (mn, 5H), 1.73 (quintet, J=7Hz, 2H), 2.23-2.33 (mn, 1H), WO 99/06397 PCT/US99/15479 00 cI 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 (in, 1H), 3.66 J=9Hz, IH), 4.08 J=7Hz, 2H), 5.95 (s, 00 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 (DCIINH3) mWe 593 0 0 ~trans. trans- 24(4 -M th oxy-3Iuo rohenyl4(7m ethoxy- 1.3c-i benzodioxl-5-yIV 1 -f(N-buty4-Np2ropylamino)crbonymethl1yrroidine 3c-arboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as a white solid. m.p. 118-120 0 C. 1 H NMR (300 MHz, CDCI3) 8 0.70-0.90 (4 triplets, J=7Hz), 1.05-1.55 (mn, 8H), 2.80-3.50 (mn, 9H), 3,55-3.65 (mn, 1H), 3.82 J= 10Hz, 1H), 3.85 3H1).

3.92 3H), 5.96 2H), 6.62 1H), 6.70 1H1), 6.90 J=8Hz, 1H).

7.08-7.22 (in, 2H).

trans. trans-4-( 1.

3 benzodioxgl-5-yl 2(4methoxyphenyl)-1 butyl-N-(4-chloroghenllaminocarbonylinethyl~Dyrroltdine- 3 carboxylic aci Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (mn, 4H), 2.66-4.00 (in, 9H), 3.81 3H), 5.95 2H), 6.77 J=7 Hz, 1H1), 6.85 J=8 Hz, 3H), 7.05 (mn, 5H), 7.33-7.42 (in, MIS (C.Q, mle 565 Analysis calcd for C 3 1H33N206CI 0.25 H3P04:

C,

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

-trans. trans-4-(l 3 Benzodioxol-5-yl 2-(4rethgxyghen~~ methyl-I .2.3 .4-tetrahydroquinli i-1 -ylcarbonlmethyflDyrrILidine,- 3

L

Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, 00300D) 8 1.27 J=7 Hz, 1.5H), 1.28 7H, 1.5-diastereomer), 1.39-1.55 (mn, 1H), 2.02-2.15 (in, 1H), 2.60- 3.25 (in, 5H), 3.33-4.00 (mn, 5H), 3.78 ts, 3H), 5.92 j=3 Hz, S-),~73 WO 99/06397 PCT/US98/1 5479 00 -399- (dd, J=8 Hz, 1H), 6.75-6.90 (in, 3H), 6.91-7.35 (in, 7H). MS (DCI) m/e 529 Analysis calcd for C 3 1H32N206.: C, 70.44; H, 6.10; N, 5.30.

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

00 5 trans. trans- 2-(3-Fluoro-4-methoxyphenyfl-4- (1 1 -r2-(N-1Drolyl-N-(2-(pilneridin- 1- 00 yflethanesulfonylamino~ethyllpyrrolidine-3-caroXylic acid 0 Using the procedures described-in Example 66, the title compound NI 0 was prepared and isolated as a white solid. m.p. 5-96 0 C. 1H NMR (CDCI3, 300MHz) 6 0.82 J=7Hz, 3H), 1.43-1.55 (mn, 4H1), 1.63-1.72 (mn, 4H), 2.29-2.38 (mn, 1H), 2.64-2.78 (in, 5H), 2.87 J=8Hz, IH), 2.95-3.04 (in, 5H), 3.20-3.30 (in, 1H), 3.32-3.43 (in, 4H), 3.54-3.63 (in, 1H1), 3.78 J=8Hz, 1 3.87 3H), 5.92 2H), 6.72 J=8Hz, 1 6.78 (dd, J=2Hz, J=8Hz, 1H), 6.88 J=8Hz, 1H), 6.94 J=2Hz, 1H), 7.08-7.20 (in, 2H). MS (DCI/NH3) Wne 620 Examle401 trans, trans- 2- (n7-Heptyfl-4-(1 .3-benzodioxol-5-yfl)-1 -(N.N-di(n- !0 butyflaininocarbonylmethyl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (CDCI3, 300 MHz) 8 0.83-0.98 9H), 1.18-1.40 (mn, 14H), 1.44-1.60 (in, 4H), 1.72-1.96 (br in, 2H), 3.12-3.45 (mn, 61H), 3.65 J 10.5 Hz, 11H), 3.76 J =11.2 11H), 3.90-4.06 (in, 2H), 4.13- 4.33 (in, 211), 5.93 2H), 6.73 J =7.8 Hz, 1 6.79 (dd, J 7.8, 1.7 Hz, 1H), 6.87 J 1.7 Hz, 1H). MS(DCI/NH3) 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.

trans. trans-4-(1 .3-Be nzodioxol-5-yfl-2-(4-methoxyphenyfl)-1 methyl-i .2.3.4-tetrahydroauinolin-1 -yflcarbonylmethyflp1yrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CID 30D) 8 0.99 1.511), 1.03 J=6 Hz, 1.5H, second diastereoiner), 2.60-4.00mn 3.78 1.5H), 3.79 (s, WO 99/06397 PCTIUS98/15479 00 -400second diastereomer), 5.92 1H), 5.93 1H, diastereomer), Cl6.65-7.40 (in, 11 MS (DCI) mle 529 Analysis calcd for C31 H32N2O6 0.8 H20: C, 68.57; H, 6.24; N, 5.16. Found: C, 70.44; H, 00 6.10; N, 5.30.

Examn[le 403 c-itrans. trans-4-(I .3-enzodioxol-5y-2(4methoxYglhenYll 0 0 garbylic 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, 2.7 J=12 Hz, 1H), 2.80 J=9 Hz, 1H), 3.09 J=9 Hz, 1H).

3.25 J=15 Hz, 1H), 3.40-3.47 (in, 1H), 3.49-3.65 (in, 3H), 3.75 (d, J=12 Hz, 1H), 3.80 3H), 5.94 6.72-6.86 (in, 4H), 7.00-7.15 (mn, 7H). MS (DCI) mWe 549 Analysis calcd for C 3 1H33N206F 0.4 C, 66.99; H, 6.13; N, 5.04. Found: C, 66.99; H, 5.94; N, 4.99.

Example 404 trans, trans-i -(-uy--3mtyhnl~mncroymty)2 4 -methoxyphenvl4 -belz f rpnI Drrolidine3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300MHz, CDC13) 867.66 (1IH, bs), 7.60 (1 H. d, J=3Hz), 7.45 (2H, 7.15 (4H, mn), 6.75 (5H, in), 3.96 (1H, d, J=lOHz), 3.78 (311, 3.74 (1iH, in), 3.59 (3H, in), 3.21 (1iH, t, J=9Hz), 3.19 (1 H, d, J=l6Hz), 2.92 (iH, t, J=9Hz), 2.70 (1H, d, J=l6Hz), 2.29 (3H, s), 1.41 (2H, in), 1.24 (211, in), 0.85 (3H, t, J=7Hz). MS (DCl, NH13) Wne 541 Anal. calcd for C33H34N20 -I H20: C, 71.21; H, 6.52; N 5.03.

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

trans. trans -1 uy-N 3-mehl1hey)a nnab ymt-l-, 4 -fluorophenyl)-4(5benzofuranvl~vrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz. CDCI3) 8 7.67 bs), 7.60 (1iH, d, J=3Hz), 7.45 (2H, in), 7.18 (3H, in), 7.12 (1H, d, J=7Hz), 6.93 (2H, in), 7C 4 Uo4, A 7 (P2H. hd). 4.02 (1 H, in), 3.77 (1 H, in), 3.59 (3H, WO 99/06397 PCT/US98/15479 00 -401in), 3.29 (1 H, in,3.19 (1H, in), 2.94 (1H, in), 2.71 (1H, in), 2.30 (311, 1.45 (2H, in), 1.26 (2H, sext, J=7Hz), 0.84 (3H, t, J=7Hz). MS (DCI, NH3) mWe 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.

00 Example 406 trans. trans-4-(1 .3-Benzodioxol.5-yfl-2-(4-mlethoxy.12henl)fl1

N-

(di ethylphelyl)aino) carbonlfrethyl yrrold in e 3 carboxylic 00 Cli Using the procedures described in Exainple'l, the title compound was prepared. 1 H NMR (300 MHz, CD3O1D) 852.27 6H), 2.81 (dd, J=8.1, Hz, 1H), 2.98 J=15.3 Hz, 1K), 3.20 J=16.6 Hz, 1H), 3.47-3.60 (in, 3H), 3.80 3H), 3.85 J=9.5 Hz, I1H), 5.91 2H), 6.73 J=7.8 Hz, 1H), 6.85 (in, 3H), 6.95 (in, 4H), 7.05 J=1.7 Hz, 1K), 7.06-7.24 (in, 6H). MS (DCI) nile 579 Anal calcd for C35H34N206 -0.15 H20 0.20 CH3C0202H5: C, 71.79; H, 6.04; N, 4.68. Found: C, 71.81; H, 5.79; N, 4.5 1.

Exain~le 407 0 trans, trans-4-(1.Dhyrbng urn5y)2(-mtoyhnl- carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H (300MHz, CDC13 8 7.73 (2H, in), 7.40-7.10 (4H1, in), 6.92 (2H, mn),6.72 (2H, d, 6.63 (11K, in), 5.40 (1H, in), 4.55 (2H, t, 4.30-4.10 (3H, in), 3.84 (3H, 3.82 (1H, in), 3.65 (1H, in), 3.39 in 3.21 (2H, t, 3.10-2.90 (2H, in), 2.26 (3H, 1.55 (2H, mn), 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.

WO "/06397 PCTIUS98/15479 00 -402l =ras. trans2(3Fluoro-4 meth _~enl 4 1 -f2-fN-jroD~yI-N-r2-(N.

N-

d-i methylamifloilethaflesulf-oflylami no) ethyll pyrro i dinle-3car oYlic 00 ai Using the procedures described inl Example 66, the title compound was prepared and isolated as a white solid. m.p. 81-82 11C. I H NMR 00 (CDCI3, 300 MHz) 8 0.80 J=7Hz, 3H), 1.43 (sextet, J=7Hz, 2. (Ni 2.24 (in, 1H), 2.36 6H), 2.66-2.76 2.83-3.04 (in, 6H), 3.18- 3.41 (mn. 5H), 3.55-3.63 (in, iN), 3.72 J=BHz, 11-1), 3.85 3H), 5.90 J=6Hz, 2H), 6.67 J=8Hz, IH), 6.78 (dd, J=2Hz, J=8Hz, iN), 6.84 (t, J=8Hz, 1H), 7.94 J=2Hz, 7.09 J=8Hz, 1H), 7.20 (dd, J=2Hz, J=l2Hz, 1H). MIS (DCI/NH3) m/e 580 trans. ras-i -(N.NQbut mncarbonylmethyl2( 4 fluoroo~e~yl bnZ f rplnlrroldIa-fle-carboxyli- aid Using the procedures described in Example 1, the title compound was prepared. 1IH NMR (300 MHz, CDCI3) 5 7.88 (18H, bs), 7.80 (28, in), 0 7.61 (1H, d, J=3Hz), 7.55 (11-H. bd, J=8Hz), 7.46 (18H, d, J=8Hz), 7.07 (2H-, t, J=8Hz), 6.76 (1 H, d, J=3Hz), 5.53 (18H, bd, J=1IHz), 4.18 (2H, mn), 3.91 (3H, in), 3.55 d, J=l6Hz), 3.30 (3H, in), 3.12 (111, dd, j=10&9Hz), 2.95 (1H, in), 1.51 (28, in), 1.31 (4H, in), 1.12 (2H, mn), 0.92 (3H, mn), 0.83 (3H, t, J=7Hz). MIS in/e (DCI, NH3) 595 Example 410 t-rans.trafls- 4 2 DihydrobeflZofuran5vl-2( 4et h hn Y-l(( carboxylc ci Using the procedures described in Example 1, the title compound was prepared. 18H NMR (300 MHz, CDC13 8 7.35 (2H, in), 7.20-7.00 (7H-, in), 6.70 (2H, d, 5.38 (18H, in), 4.55 (2H, t, 4.05 (18H, in), 3.64 (28, in), 3.45 (18H, mn), 3.21 (28, t, 2.95 (iH, in), 2.75 (1H, in), 2.63 (2H, 2.38 (2H, in), 2.27 (3H, 1.43 (2H, in), 1.30 (2H, in), 1.22 (3H, t, 0.89 (3H, t, MS (DCI/NH3) m/e 541 Anal WO 99/06397 PCF/tJS98/15479 00 -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.

Exmpe 1 00 trans, trans-4-(l .2-Dihydrobenzof uran-5-yl-2-(4-f luoroghpnflt)- 1- (N.N-di(n-butyflaminocarbonylmethyl)-.Dyrrolidine-3-caboxylic acid Using the procedures described in Example 1, the title compound 0 7.18 (1 H, dd, J=8, 7.00 (2H, t, 6.72 (1 H, d, 4.53 (2H, t, (1 3.92 (1IH, in), 3.65 (1 H, mn), 3.42 (3H, in), 3.19 (2H, t, 3.15- 2.90 (6H1, in), 1.43 (3H, in), 1.25 (3H, in), 1.10 (2H, mn), 0.90 (3H. t. J=8), 0.83 (3H, t, MS (DCI/NH3) m/e 497 Anal calcd for C29H37FN204 '0.25 H20: C, 69.51; H, 7.54; N, 5.59. Found: C, 69.45; H, 7.60; N, 5.44.

Example 42 trans, trans-4-(1 .2-Dihydrobenzofuran-5-yl-2-(4-fluoroheflYl)-l ((NbtlN(-ehlhnlaio~abnlmty)2roiie3 carboxylic acid I 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 mn), 6.91 (2H, in), 6.72 (3H, d, 4.54 (2H, t, 4.00 (1H, mn), 3.60 (3H, in), 3.45 (1 H, mn), 3.19 (2H, t, 3.11 (2H, in), 2.84 in), 2.67 (1H, bd, J=18), 2.26 1.42 mn), 1.25 (2H, mn), 0.88 (3H, t. J=8).

MS (DCI/NH3) m/e 531 Anal calcd for C 3 2H35FN204 0.25 C, 71.82; H, 6.69; N, 5.23. Found: C, 71.66; H, 6.55; N,.03 Exmpli,413 trans. trana-4-( Indan-5-y l-2-(4-nethoxyphenYlY' N-di(nbutyflaminocarbonylnethyl).Dyrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I 1 H N MR (300 MHz, CDCI3 8 7.32 (3H, in), 7.18 (2H, in), 6.85 (2H, d. 3.83 (IH, in), 3.79 (3H, 3.67 (1H, in), 3.50-3.20 (4H, in), 3.20-2*.92 (4H, in), 2.87 (5H1, in), 2.79 (1H, bd, J=15), 2.06 (2H1, in), 1.43 (2H, mn), 1.27 (4H, in), 1.08 (2H, in), 0.138 (3H, t, 0.82 (311, t, WO 99/06397 PCT/US98/15479 00 c-I -404- S MS (DC VNH3) We 507 Anal calcd for C31H42N204:

C,

73.49; H, 8.36; N, 5.53. Found: C, 73.18; H, 8.29; N, 5.17.

00 Exmpe414 trans. trans-2-(4-Methoxyghenyl)4(34difluoroPhenYl)-I -f(N-butyt-

N-(

3 -methylohenyl)amno~~carbonylmethyI1Dyrroldine3-arboxylic 00

Q

Using the procedures described in Example 1, the title compound cIwas prepared. I H NMR (300MHz, CDC13) 5 0.86 J=7Hz, 3H), 1.10-1.35 (in, 2H), 1.35-1.52 (in, 2H), 2.29 3H), 2.63 J=l3Hz, IH), 2.76 (t, J=7Hz, 1H), 3.06-3.20 (mn, 2H), 3.42-3.53 (in, 1H), 3.50-3.64 (mn, 3H), 3.80 3H), 3.86 J=9Hz, 1H), 6.66-6.82 (in, 4H), 7.02-7.22 (mn, 6H), 7.30-7.40 (in, 1H).

trans. trans-i -(N-Butyl.N-(3-chlorophelyflainocarbonYlinethyl- 2 (4f~rpey)4(-ezfrnl1yrldn--abxlc acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 7.64 (1 H, d, J=2Hz), 7.61 (1IH.

d. J=3Hz), 7.47 (1K, d, J=8Hz), 7.41 (1H, dd, J=8&3Hz), 7.30 (1K, dt, J=8&2Hz), 7.21 (1H, d, J=8Hz), 7.19 (2H, mn), 7.00 (1H, bs), 6.94 t, J=8Hz), 6.83 (1H, bd, J=8Hz), 6.74 (1H, dd, 3.96 (1H, d, J=lOHz), 3.75 (IH, ddd, 6, 5&3Hz), 3.59 (3H, in), 3.23 (1K, t, 3.18 (1H, d, J=l6Hz), 2.92 (11H, dd, J=10&9Hz), 2.69 (1K, d, J=l6Hz), 1.41 (2H, in), 1.23 (2H, in), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) 549, 551 Anal. calcd for C31 H3OCIFN20O C, 67.82; H, 5.51; N, 5.10.

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

Exampile 41 trans, trans-4-(l .3Benzodioxol-5yfl2(4methgxYl~he-nyl)- Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 M~z, CDC13 8 (rotamer) 7.40-7.20 (5H, in), 7.13 (2H, in), 6.98 (2H, in), 6.93-6.60 (7H, in), 5.93 (1H, d, 5.88 (5.85) a, 4.90 (4.50)-(111' I 4, d 6,15).

WO 99/06397 PCT/US98/15479 00 -405- S3.77 (3.73) (3H, 3.72 (11H, in), 3.60 in), 3.53-3.20 mn), 3.15- *2.75 (4H, in), 1.60-1.20 in), 0.83 (0.64) (3H, t, MS (DC1/NH3) m/e 623 Anal calcd for C 3 7H38N207 .0.25 H20: C, 70.85; H, 6.19; N, 4.47. Found: C, 70.68; H, 6.10; N, 4.42.

00 Examgl~a417 0 trans, trans-44-( Dihdro -zfralY)(_4-ethyl ghenyl)- 00 (2-gentyfl.-W(4-fluoro- 3 m ethyl phenyl)aino)carbonyl m ethYl)PYrroli dine3carboxylic -acid Using the procedures described in Example'-1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 7.30 (1 H, bs), 7.20-7.00 mn), 6.87 (1 H, mn), 6.73 (2H, d, 6.57 (1 H, in), 4.81 (1H. in), 4.55 (2H, t, 3.92 (1 H, bd, J=1 3.60 (1 H, in), 3.43 (1 H, in), 3.18 (2H, t, J=9), 3.17 (1 H, in), 3.06 (1 H, dd, J=1 5, 2.88 (1 H, dd, J=1 1, 2.61 (2H, q, 5J=8), 2.59 (1 H, in), 2.18 (3H, in), 1.40-1.10 (4H 1.22 (3H. t. J=9), 1.00-0.80 (6H, in). MS (DCI/NH3) W/e 573 Anal calcd for 0 3 5H41FN204 0.75 H20: C, 71.71; H, 7.31; N, 4.78. Found: C, 71.56;

H,

7.33; N, 4.56.

0 Exmpe-41-a trans. trans-2-4-MethoxphenYl- 4 nzodioxol5y/l-1 propyl-N-r 2 -pyriinidinylpiino~ethylpyrrolidne3cabxlc ai Ethyl 2-(4-inethoxyphenyl)- 4 ,3-benzodioxol-5y)-(-2-(Npro pylami no) propyl]pyrroli di ne-3carb oxyl ate, prepared by the procedures of Example 61B (300 mg), 138 mg of 2-bromopyriinidine, and 150 mg of diisopropylethylainine 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 ing of the title compound. 1 H NMR (300 MHz, CDC13) 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 (m 3.60-3.70 (mn, 3H), 3.75 3H), 5.95 2H), 6.34 (t, J=4Hz, 1H), 6.65 J=BHz, 1H), 6.75-6.82 (in, IN), 6.78 J=9Hz, 2H), 6.96 J=2H-z, 1H), 7.27 J=9H-z, 2H), 8.20 J=4Hz, 2H).

WO 99/06397 PCT/US98/15479 00 c-I -406cItrans -trans-4-(1 .3 -B e nzod Io xol-5.yfl. 2- (4-meth Qxjph enl)l- 1 -3.

butyl-2-chloro-hept-2-efl-1 .yItoyrrolidine-3-carboxylic -acid 00 Using the procedures described In Example 1, the title compound C was prepared. 1 HNMR (300 MHz, CD3OD) 5 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 (mn, N- 2H), 2.78 (dd, J=6.6, 9.2 Hz, 1 2.95 J=9.2 Hz, 1IH), 3.32-3.37 (mn, 00 2H), 3.49 (mn, I1H), 3.70 J=9.2 Hz, 1 3.77 3H), 5.91 (in, 2H), 6.72 c-I J=8.1 Hz, 1H), 6.85 (dd, J=1.9, 8.1 Hz, 1H), 6.89 (mn, 2H), 7.08 (d, Hz, 1H). 7.36 (in, MS (DCI) Wle 528 Anal calcd for C3OH-3BCINO5 0.25 H20: C, 67.66; H, 7.29; N, 2.63. Found: C, 67.62; H, 7.18; N, 2.40.

trans. trans-4-(1 .2Dihydrobenzof uran-5.l)2(4methoxynhpnyl) -m (((N.-(2-oentyfl)N-(4-fIUjoro- 3 methylnhenvflpain~carbonlfmethyl~Dyrrolidine3carbgxylig acid Using the procedures described in Example 1. the title compound was prepared. 1 H NMR (300 MHz, CDC13 7.28 (1 H, bs), 7.15 (3H, mn),- 6.90 (1H. in), 6.77 dd, J=9, 6.71 (2H, d, 6.56 (1 H, in), 4.80 (1 H, in), 4.53 (2H, t, 3.92 (1 H, mn), 3.79 3.60 (1IH, in), 3.45 (1H, in), 3.19 (211, t, 3.18 in), 3.03 (1H, dd, J=15, 2.85 (1, in), 2.55 in), 2.18 (3H, in), 1.40-1.05 (4H, in), 1.00-0.80 (6H, in). MS (DCIINH3) rn/e 575 Anal calcd for C 34 H39FN205 0.35 H20: C, 70.29; H, 6.89; N, 4.82. Found: C, 70.37; H, 6.92; N, 4.30.

Example421 trans.tlrans-4- (1 2 D ihyd roe n zof uran5-yl)2 -(4-mehoxyPtanyfl) 1 (((N-butyl.N-(3-chlorophenyl~amIio)carbonyl)inethvI)Pyrrglidine 3 carboxyLiac acd Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 7.29 (1 H, d, 7.25-7.05 in), 6.98 (1 H, bs), 6.80 (2H, in), 6.72 (2H, d, 4.53 t, J=9).

3.85 (1H, d, J=10), 3.79 3.58 (3H, in), 3.42 dd, J=10, 3.18 (4H, in), 2.87 in), 2.66 (1H, in), 1.40 (2H, in), 1.25 (2H, in), 0.86 (3H, WO 99/06397 PCT/US98/15479 00 -407t, MS (DCI/NH3) m/e 563 Anal calcd for 032H35ClN205 N- 0.25 H20: C, 67.72; H, 6.30; N, 4.94. Found: C, 67.72; H, 6.21; N, 4.55.

00Exml42 C trans, trans-4-(l .3-Benzodioxol-5yl-2(5-ethylfuran2iyll di(n-butyflaminocarbonylmethyl)-1DYrrolidife3carboxylic acid Using the procedures described in Example 1, the title compound 00 was prepared. 1 H NMR (300 MHz, CDC13 8 7.77 (1 H, bs), 7.11 (1 H, d, 7.02 (1 H, dd, J=9, 6.82 (1 H, d, 6.52.(l1H, d, 6.08 (1 H.

d, 5.98 (2H, 5.80 (1H, d, 4.70 (1H, bd, J=15), 4.37 (2H, in), 3.70 (2H, in), 3.39 (2H, mn), 3.20 (1 H, mn), 3.10-2.82 (2H, in), 2.76 (2H, q, 1.45 (2H1, in), 1.32 (3H, t, 1.30-1.10 (6H, in), 0.87 (3H. t.

0.85 (3H, t, MS (DCI/NH3) Wne 499 Anal calcd for C28H:38N206 1.75 HCI: C, 59.80; H, 7.12; N, 4.98. Found: C, 59.51; H, 56.96; N, 4.88.

trans. trans7!4-( 1.2Dhdoezo urn5v)2(-loohnl (((N-(2-pentyfl-N-(4-fluoro-3o methyllphenyflaino)carbonyflmethvl)12yrroidine 3 carboxylt-c ai Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 7.30-7.10 (4H, in), 6.92 (3H, mn), 6.73 (2H, d, 6.59 (1H, mn), 4.80 (1H, in), 4.53 (2H. t, 4.00 (1H, bd, J=10), 3.62 (1H, in), 3.45 (1H, in), 3.22 (1H, in), 3.21 (2H. t, 3.02 (1H, dd, J=15, 3.85 (1H, t, J=10), 2.58 (1H, bd, J=18), 2.20 (3H, bs), 1.40-1.30 (3H, mn), 1.15 (1H, in), 1.00-0.80 (6H, in). MS (DCI/NH3) m/e 563 Anal calcd for C 3 3H36F2N204: C, 70.44; H, 6.45; N, 4.98. Found: C, 70.06; H, 6.47; N, 4.71.

Example 24 trans, trpns-4-(1 .2Dihydrobezofur-an5yl244iiuorophegnYl)- 1(N- but yl -N hioropDhen vi ~a mlno 'carbon yl 'methyl )oy r ro lid in e-3- Using the procedures described in Example l, the title compound was prepared. 1 H NMR (300 MHz, CDC13 5 7.30 (2H, in), 7.25-7.10 (4H, WO 99/06397 PCTIUS98/15479 00 c-I -408in), 6.95 (3H, in), 6.82 (1 H, bd, 6.73 (1 H, d, 4.55 (2H, t, J=9), 3.92 (11H, bd, J=11), 3.60 (3H, in), 3.43 (1 H, dd, J=9, 3.21 (2H, t. J=9), 3.16 (2H, mn), 2.87 (IH, mn), 2.69 (1H. mn), 1.42 (2H, in), 1.26 (2H, in), 0.87 00 (3H, t, MVS (DCI/NH3) m/e 55*1 Anal calcd for C31 H32CIFN204 0.25 H20: C, 67.02; H. 5.90; N, 5.04. Found: C, 66.98; H, 5.7 1; N, 4.76.

00 Example425 N- trans. trans-4-(l-.-iyrbno urn5v)2(-tvgey) Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 6 7.30 (1IH, in), 7.21 (18H, d, 7.15 (2H, in), 7.09 (4H, bs), 6.96 (18H, bs), 6.80 (1 H, bd, 6.73 (1 H, d, 4.54 (2H, t, 3.89 (1 H, bd, J=1 3.60 (3H, in), 3.43 (1H, in), 3.22 (2H. t, 3.18 (2H, in), 2.92 (111, mn), 2.72 (1 H, mn), 2.62 (2H, q, 1.41 (2H, in), 1.26 (2H, mn), 1.23 (3H, t, 0.87 (3H, t, MS (DCI/NH3) mWe 561 Anal calcd for C33H37C1N204 0.25 H20: C, 70.08; H, 6.6B; N, 4.95. Found: C, 70.13; H, 6.59; N, 4.65.

trans-.1trans-i -(-uy--3clrlhnl~abxmdmeU:-LupYIP oiine3carboXylic cid Using the procedures described in Example 1, the title compound was prepared. 18 NMR (300 MHz, CDCI3) 8 7.67 (18, bs), 7.60 (18, 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 (18, bs), 6.76 (48, in), 3.88 (1H, d, J=lOHz), 3.75 (1H, ddd, J=6, 5&Hz), 3.59 (2H, in), 3.53 (1H, dd, J=10&3Hz), 3.22 (1H, t, J=9Hz), 3.19 (18, in), 2.96( 18, in), 2.70 (18, d, J=l6Hz), 1.42 (2H, mn), 1.26 (28, mn), 0.87 (3H, t, J=7Hz). MS (DCI, NH3) m/e 563, 561 Anal. calcd for

C

3 2 H-33ClN2O5 -0.5 H20: C, 67.42; H, 6.01; N, 4.91. Found: C, 67.45;

H,

5.82; N, 4.68.

WO 99/06397 PCTIUS98/15479 00 -409- Examgl427 trans, trans-4- (1 .3-Benzodi oxol-5-yfl-2-(4-m ethoxylhenl)lI cyclohexyl-N-butylamilo~ca rbonyfl)methyl)pyrrol idile-3a rboxy i c 00 5 Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) (rotamer) 8 0.78 (0.86) 3H, J=7Hz), 0.90-1.90 (envelope, 14H), 2.69 (2.80) 1H, J=l2Hz), 2.9-3.8 00 (envelope, 101-), 3.78 (3.80) 3H), 5.92 2H), 6.72 1H1, J=9Hz) 6.86 (in, 3H) 7.03 1H, J=6H-z), 7.34 (in, 2H). MS (DCI/NH3) m/e 537 (1 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.

trans, trains-4-( 13Bezdoo5-)--4thlhnv- 1 awi Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) 8 0.86 3H, J=7Hz), 1.22 (t, 3H, J=7Hz), 1.25 (in, 2H), 1.43 (in, 2H), 2.26 3H), 2.6 2H, J=7Hz), !0 2.68 1H, J=l2H1z), 2.86 1H, J=8Hz). 3.19 2H, J=7Hz), 3.44 (dd, 1H, J= 3Hz,lOHz), 3.59 (in, 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 1H, J= 8H-z). MS (DCI/NH3) m/e 543 Anal. calc'd for C33H38N205 0.60 H20: C, 71.61;.H, 7.14; N, 5.06. Found: C, 71.57; H, 6.80; N. 4.87.

trans. trans-4-(Benzgf uran-5-y)-2(4-pthylghenyl)-1 methyl phenyl)-Nbutylaino) carbofyl)inethvl)P2yrrolidne- 3 -carbo xyli Using the procedures described in Example 1, the title compound was prepared. 1 NMR (300 MHz, CDCI3) 8 0.90 3H, J=7H-z), 1.30 (t, 3H, J=7H-z), 1.31 (in, 2H), 1.43 (mn, 2H1), 2.27 3H), 2.73 2H, J=7H-z), 3.15 2H, J=l7Hz), 3.61 2H, J= 8Hz), 3.82 (mn, 2H), 4.00 1 H, 12H-z), 4.26 (mn, 2H), 5.53 (br d, 6.54 (br s, 2H1), 6.76 1H, J= 2Hz), 7.14 (mn, 3H), 7.28 1H), T40 (mn, 311), 7.48 1H1, J= 8Hz), 7.63 111, WO 99/06397 PCT/US98/15479 00 c~Kl -410- S J=2Hz), 7.73 1H). HRMS. calc'd for C34H39N204 539.2910.

Found: 539.2891 00 ExampIl43 trans. trans-4-( 1.4-Benzodioxan-6-yfl-2-(4-ethylphenl)l I phenyl I-N -butyl ami no) carbolyl)m ethyl pyrrol dine3ca rboxyli 00 Using the procedures described in Example 1, the title compound N- was prepared. I H NMR (300 MHz, CDCI3) 8 0.87 Qt, 3H, J=7Hz),* 1.22 (t, 3H, J=7Hz), 1.24 (in, 2H), 1.42 (in, 2H), 2.30 3H), 2.61 2H, J=7Hz), 2.67 1H, J=l4Hz), 2.86 1H, J= 8Hz), 3.18 2H, J=7Hz), 3.41 (dd.

1 H, J=4,lOHz), 3.59 (in, 3H), 3.93 1H, J=lOHz), 4.25 (in, 4H), 6.74 (br s, 2H), 6.80 1H, J=8Hz), 6.93 (dd, 1H, J=2Hz,8Hz), 6.99 1H, J=2Hz), 7.07 (in, 5H1), 7.17 1H, J=8Hz). MS (DCI/NH3) We 557 Anal.

calc'd for C34H40N205 -0.40 H20: C, 72.42; H, 7.29; N, 4.97. Found: C, 72.49; H, 7.16; N, 4.62.

Exmple 431 trans.-trans-24(3-Flu oro-4-Methogyphenyl 4 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 80-82 c 0 C. I H NMR (CDC13, 300 MHz) 8 0.69 J=7Hz, 3H), 1.37 (sextet, J=7Hz, 2H), 2.09- 2.17 (in, 1H), 2.24 3H), 2.53 6H), 2.54-2.64 (in, 1H), 2.73-2.86 (in, 211), 3.02 (sextet, J=7Hz, 2H), 3.13-3.28 (in, 3.44-3.53 (in, 1H),.

3.57 J=9Hz, 1H), 3.89 3H), 5.94 2H), 6.74 J=8Hz, 1H), 6.78 (dd, J=2H-z, J=8Hz, 1H), 6.85 2H), 6.92 J=8Hz, 1H), 9.94 J=2Hz, 1H), 7.06 J=8Hz, 1H), 7.13 (dd, J=2Hz, J=12Hz, 1H). MS (DCI/NH3) Wne 627 trana. trans-2-(4-Methoxyphenl)4-(3.4-difluoropherlyl)-l -(N-b-utyl-

N-(

3 -ch o ropheflyfl)aino) carbo nl miethylpyrro i din e3carboxylic -acid Using the procedures described in Example 1, the title compound wa~ Wrp~d KiLJNAD ('fqnn NA7 rnnljq) 8 0.86 J=7Hz. 3H), 1.18-1.32 WO 99/06397 PCT/US98/15479 00 -411- (in, 2H), 1.35-1.48 (in, 2H), 2.64 J=13Hz, 1H), 2.71 J= 7Hz, IH).

3.08-3.18 (in, 2H), 3.42-3.48 (in, IH), 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).

00 'xml 3 transa.trn--3Fuoo4mtoy gy)4(.3.benzodioxol-5-yfl- 00 abx&-aQ Using the procedures described in Example 1, the title compound D was prepared. I1 NMR (CD3OD, 300 MHz) 8 0.80 3H, 1.47 (bd hex, 2H, 2.15 (pen, 2H, 2.32 (mn, 1H), 2.7-3.2 (in, 9H), 3.46 (dd, 1H, J=4, 10), 3.57 (in, 1H), 3.64 2H, 3.67 1H, 3.86 3H), 5.92 2H), 6.74 I1H, 6.84 (dd, I1H, J=2, 6.96 1 H.

7.06 1 H. 7.18 (in, 2H). MS (DCI/NH3) We 585 (M+H: s 35CI)+; 587 3 7 Anal calcd for C 27 H34N207C1FS: C, 55.43; H, 5.86; N, 4.79. Found: C. 55.65; H, 5.81; N, 4.70.

trans. trans-2-(3-Fluoro-4meth xylhenyl- 4 Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.79 3H. 0.84 3H, J=7),1.68 (hept, 1H, 2.18 (pen, 2H, 2.8-3.4 (mn, 1OH), 3.5-3.8 (in, 3H), 3.65 2H, 3.90 3H), 5.94 2H), 6.77 1H, J=8), 6.87 (dd, 1H, J=2, 6.99 1H, 7.13 1H, 7.27 (mn, 2H).

MS (DCI/NH3) Wne 599 Anal calcd for C 28 H36N207CIFS -0.3 TFA: C, 54.24;, H, 5.78; N, 4.42. Found: C, 54.19; H, 5.71; N, 4.01.

Example, 43 trans. trans-2-PrgoOxyiethvl 4 -ben zodioxol51l)l I-(NN-dkiLn butyflaimnlcarbonyLiethyl)pyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (CDCI3, 300 MHz) 8 0.87-0.98 (in, 9H), 1.21-1.39 (in, 4H), 1.43-1.57 (in, 4H), 1.58-1.70 (in, 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, 1H), 3.80- WO 99/06397 PCTIUS98/15479 00 -412- S 4.20 (in, 4H), 5.93 2H), 6.73 J =7.8 Hz, I1H), 6.84 (dd, J 8.2, 1.7 CI Hz, 1H), 6.93 J 1.7 Hz, I1H). MS(DCI/NH3) mWe 477 Anal calcd for C2*6H-4ON2O6-0.50 TFA: C, 60.77; H, 7.65; N, 5.25. Found: C, 00 60.73; H, 7.74; N, 5.22.

Example 46 00trans, trans-2-(3-Fluoro-4-methgxyghenviV- 4 0 Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. in.p. 65-67 OC. I 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 (in, 3H), 2.24-2.33 (in, 1H), 2.68-2.93 (in, 2.98-3.12 (in, 2H), 3.15-3.35 (mn, 2H). 3.43 (dd, J=3Hz, J=9Hz, 3.52- 3.58 11H), 3.65 J=l2Hz, 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 Example 437 trans. trans!2-(4*-Metho~xy3-fluoroghenyl) 4-(7-iethoxyl 3ben zodipoxl- 5-yi)- 1 -f 2-(N-p ro pyI-N(n De ntan esuf o nyl)aino) ethylipyrrolidine3carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (300MHz, CDC13) 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 (in, 2H), 2.22-2.34 (in, 1H), 2.30-2.95 (in, 5H), 2.95-3.10 (in, 2H), 3.15-3.33 (in, 2H), 3.45 (dd, J=3Hz, 9Hz, 1H), 3.47-3.56 (mn, 1H), 3.65 J=9Hz, I 3.88 3H), 3.94 3H), 5.95 2H), 6.55 1 6.65 1 H), 6.92 J=7H, 11H), 7.11 J=9Hz,1H), 7.17 J=l2Hz, 1H).

WO 99/06397 PCT/US98/15479 00 -413- -trans, trans--2-(3-Eluoro-4methoxyphenyl)- 4 I -r2-(N-prolyl-N-(2, 2 .3.3.3pentafluororoxyethalesulonl)amino~IethyI1pyrrolidine- 3 00 caboyljici Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 63-64 OC. 1 HNMVR N0 (CDCI3, 300MHz) 8 0.82 J=7Hz, 3H), 1.45 (sextet, J=7Hz, 2H), 2.24- 2.33 (in, 1H), 2.70-2.82 (in, 1H), 2.85-3.09 (in, 5H), 3.14-3.28 (in, 4H), 3.43 (dd, J=3Hz, J=9Hz, 1H), 3.52-3.58 (mn, 1H), 31~5 J=9Hz, 1H), 3.87 3H), 3.92-3.98 (in, 3H), 5.94 2H), 6.74 J=8Nz, 1N), 6.82 (dd, J=2Hz, J=8Hz, 1H), 6.92 J=8Hz, 1H), 6.97 J=2Hz, 1H), 7.10 (d, J=9Hz, 7.17 (dd, J=2Hz, J=l2Hz, 1H). MS (DCI/NH3) in/e 685 ExamplA 43 trans-trans-2-(l .4Benzodioxaf-6yP-4(7methgxy-1.3-benzodioxol- -y fl-lg .Qi Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CDCI3) 8 0.81 J=7Hz, 3H), 0.90 J=7Nz, 3H), 1.23-1.36 (in, 4H), 1.45 (sextet, J=7Hz, 2H), 1.65-1.78 (mn, 2H), 2.20- 2.30 (in, 1H), 2.30-2.95 (in, 5N), 2.95-3.10 (in, 2H), 3.15-3.35 (in, 2H), 3.42 (dd, J=3Hz, 9Hz, 1H), 3.46-3.56 (mn, 1H), 3.59 J=9Hz, 1H), 3.91 3H), 4.24 4H), 5.95 2H), 6.57 I 6.68 1iH), 6.82 (d, J=8Hz, 1H), 6.88 (dd, J=2Hz, 8Hz, 1H), 6.95 J=2Hz, 1H).

trans, trans-4-(l 3 Benzodioxol5vl2(4methoxy hen~yl)l-(((Nbutyl 4 -met hoxyb e nfl aino) carbonyl)etvl Drrolidine- 3 cgbxlcai Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDC13 8 (rotamer) 7.32 (1 H, d, J=1 0), 7.22 (iN, in), 7.10 (1H, d, 7.03 (6.98) (iN, d, 6.90-6.80 (4H, in), 6.79 (2H, d, 6.77 (1H, t, 5.8.5 (2H, 4.92 (4.10) (1H, d, J=15), 4.42 (4.22) (iN, d, J=15), 3.81.(iN, in), 3.79 (3.78) (3H, 3.76 (3H, 3.62 (1iH, 3.43 in), 3.30-2.70 (5H, in), 1.42 (1H, in), 1.23 WO 99/06397 PCTIUS98/15479 00 c-I -414- (2H, in), 1.01 (1 H, in), 0.83 (0.75) (3H, t, MS (DCI/NH3) W/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.

00 trans. trans- Fl uoro-4-m etho xyphelyfl- 4 1 .3-b enzodi oxol 00 0 Using the procedures described in Example 66, the title compound 0 was prepared. 1H NMR (CD3OD, 300 MHz) 8 0.76 3H, 0.84 3H, 0.92 3H, 1.36 (in, 4H),1.70 (in, 3H), 2.90 (mn, 2H), 3.02 (mn, 2H1), 3.1-3.8 (in, 7H), 3.84 2H-, 3.91 3H), 5.96 2H), 6.80 (d, I1H, 6.88 (dd, 1 H, J=2, 7.00 I1H, 7.19 1 H, 7.35 (in, 2K). MS (DCI/NH3) Wne 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-f 1.3Bnoixl5 )2-4mtoyjey) 1 U sing 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, 4H), 2.70-2.90 (in, 3.13 J=8 Hz, 1K), 3.40-3.90 (in, 6H), 3.79 3H1), 5.93 2H), 6.75 J=8 Hz, 1 6.80-7.20 (in, 9H), 7.40 (in, 1KH). MS (DCI) in/e 549 Anal calcd for C31 H33N206F -0.8 C, 66.13; H, 6.19; N, 4.98. Found: C, 66.21; H, 5.83; N, 4.84.

Example 443 trans. trans-4-( 1.3Benzodioxgl.5-yfl-2-(4-f luorophenl)ll -(N-butylch oroph enyl amino) carbo nyl methylrDyrrol idi ne3carboxylic acid Using the procedures described in-Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.65-2.85 (in, 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, 31H), 7.33-7.45 (mn, MVS (DCI) m/e 553 Anal calcd for WO 99/06397 PCTfUS98/15479 00 ci -415-

C

3 OH3ON205FCl: C. 65.16; H, 5.47; N, 5.07. Found: 0, 65.37; H. 5.41; N, 4.98.

00 Example 444 trans. trans-4-(l .3-Benzodioxol.5-yfl-2-(4-methoxyphe-nyfl- 1 butyl-N-(3.4-dimethoxybenzyl~amino~carbonylmethyflDyrrolidile- 3 00 0 Using the procedures described in Example 1, the title compound 0 was prepared. I H NMVIR (300 MHz, CDC13 8 (rotarner) 7.33 (1 H, d, J= 0 7.23 (IH, in), 7.03 (6.97) (1H, d, 6.90-6.60 (6H, in), 6.47 (1H, in), 5.93 (2H, mn), 4.83 (4.09) (IH1, d, J=15), 4.45 (4.22) (1H, d, J=15), 3.83 (3.86) (3H, 3.79 (1H, in), 3.77 (3.76) (3H, 3.75 (3.65) (3H, 3.60 (1 H, in), 3.43 (2H, in), 3.28 (1 H, in), 3.20-2.70 (4H, rn), 1.43 (1 H, in), 1.23 (2H, in), 1.02 (1 H, in), 0.84 (0.77) (3H, t, MIS (DCI/NH3) m/e 605 Anal calcd for C34H40N208: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.28; H, 6.63; N, 4.38.

trans, trans-4-(l .3-BenzodioxoI-5-yfl-2-(4-nethoxyphefl)l 1 0 butyI-N-(2-methoxybenzylaino~carbonyflinethyflD1yrrolidine- 3 Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 8 (rotamer) 7.33 (1 H, d, J=1 0), 7.11 (2H, mn), 7.03 (1 H, dd, J=8, 6.90-6.60 (7H, in), 5.93 (2H, in), 4.83 (4.15) (1H, d, J=15), 4.47 (4.30) (1H, d, J=15), 3.81 (1H, in), 3.78 (3.73) (3H, 3.72 (3H, 3.59 (1IH, in), 3.43 (2H, in), 3.30 (1H. in), 3.20-2.70 (4H, in), 1.42 in), 1.23 (2H, mn), 1.01 (1H, in), 0.83 (0.77) (3H, t, J=8).

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

WO 99/06397 PCT/US98/15479 00 c~Kl -416- Examplp,46 CItrans. trans-4-(l Ben zodi oxol meth oxyphel)-1 butyl -N methoxyb en zylam in olca rbollm ethyflpyrrol idi ne- 3 00 cabxlcai 5 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, 7.13 (1H, d, 7.16 (1H, dt, J=8, 7.03 (1H, dd, J=10, 6.90-6.60 00(6H, in), 6.50 (1H, in), 5.94 (2H, mn), 4.82 (4.19) (1H, d, J=15), 4.50 (4.23) c-I (1H, d, J=15), 3.78 (3.76) (3H, 3.77 (1H, in), 3.75 (3.67) (3H, 3.59 0 (1H, in), 3.57-3.35 (2H, mn), 3.25 (1H, in), 3.20-2.70 (4H, in), 1.43 (1H, mn), 1.23 (2H, in), 1.02 (1H, mn), 0.84 (0.77) (3H, t, MS (DCI/NH3) Wne 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 44 trans. trans-2-(3-Fluoro-4-mthoxCYphgnyl'-4-( 1.3-benzodioxol-5-fl)- 1 N-(2-methoxyethyl')-N-(3w chloroprolanesulfgnylpflilo~ethyI)flyrrlidine 3 -crboxylic acid Using the procedures described in Example 66, the title compound !0 was prepared. I 1 H NMR (CD3OD, 300 MHz) 8 2.15 (pen, 2H, 2.33 (in, 1H), 2.81 (in, 2H); 2.93 1H, 3.1-3.6 (in, 1OH), 3.24 3H); 3.65 2H, 3.70 1 H, 3.87 3H), 5.92 2H), 6.74 1 H, 6.84 (dd, 1 H, J=2, 6.97 I1H, 7.07 1 H, 7.17 (in, 2H). MS (DCI/NH3) in/e 601 (M+H) 4 Anal calcd for C 27 H34N208C1FS: C, 53.95; H, 5.70; N, 4.66. Found: C, 53.65; H, 5.49; N, 4.26.

trans, trans-2 Flu oro-4-m eth oxyphenyl 4 (l.3-be nzod ioxol- 1 2 -(N-(2-inethoxyethyW)N-(pentfle~ulfonlIamin)ethyl)pyrrolidine- 3-carboxylic, acid Using the procedures described in Example 66, the title compound was prepared. 1 H NMR (CD3OD, 300 MHz) 8 0.93 (mn, 3H), 1.34 (mn, 4H), 1.69 (in, 2.33 (in, 1 2.75-3.1 (mn, 7H), 3.23 3H), 3.3-3.6 (in, 6H), 3.70 1 H, 3.86 3H), 5.92 6.74 I1H, 6.84 (dd, I H, J=2, 6.97 I1H. 7.07 (t1, 1H, 7.18 (in, 2H). MS WO 99/06397 PCTfUS98/15479 00 -417- (DCI/NH3) mle 595 Anal calcd for C29H3gN2OBFS: C, 58.57; H, 6.61; N, 4.71. Found: C, 58.21; H, 6.29; N, 4.29.

Examgle449 005 trans. trans-4-(1 Ben zodio xo I-5-yfl-2-(4-methoxyp henyl)--1 he pt yl)-N- (4-flu oro -3methylphenylamino~carbonylmethyl~yrrolidine-3-crboxyic acid 00 Using the procedures described in Example 1, the title compound was prepared. III NMR (300 MHz, CD3OD) S 0.89 (in, 6H), 1.18-1.36 (mn, 0 2.15 (bs, 1.5 (CH3 rotamer)), 2.28 (bs, 1.5 (CH3 rotamer)), 2.64 (t, J=14.9 Hz, 1H), 2.82 (in, 1H), 3.07-3.29 (in, 2H), 3.32-3.41 (in, 1H), 3.53-3.60 (in, 1H), 3.70-3.79 (in, 11H), 3.79 3H1), 4.68 (in, 1H), 5.92 (in, 2H), 6.69-6.90 (in, 6H1), 6.93-7.07 (in, 4H). MS (DCI) mle 605 Anal calcd for C35H41 FN206: C, 69.52; H, 6.83; N, 4.63. Found: C, 69.31; H, 6.78; N, 4.35.

Eample 450 trans, trans-4-(1 .3.Benzodioxol-5-y)-2-(4-methoxyphenyfl- 1 non yl N-(4-fl u oro -3- ?0 miet hyl 1henyllam in o)carbonyfl)methyl~yrrol idine-3-carboxyli c acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 0.81-0.90 (mn, 6H1), 1.30 (in, 12H), 2.14 1.5 (CH3 rotainer)), 2.30 1.5 (CH3 rotamer)), 2.60 (t, J=14.8 Hz, 11H), 2.80 (mn, 1H), 3.09-3.24 (mn, 2H), 3.33-3.42 (in, 1H), 3.50-3.55 (mi, 1H), 3.65-3.77 (in, 1H), 3.79 3H), 4.64 (mn, 1H), 5.93 (mn, 2H), 6.70-6.84 (in, 5H), 6.91-7.13 (in, 5H). MS (DCI) in/e 633 Anal calcd for C37H45FN206: C, 70.23; H, 7.17; N, 4.43. Found: C, 70.14; H, 7.13; N, 4.19.

Examl~A 41 trans. trans-4-(1 .3-Benzodioxol-5-yfl-2-(4-inethoxyphenyl)-1 nonylamino~carbonylm ethyl) yrrolidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 0.80 J=7.0 Hz, 3H), 0.84 J=7.1 Hz, 1.15-1.55 (in, 12H), 2.88 J=15.9 Hz, 1H), 3.07 (in, 211), 3.26 J=16.3 Hz, 111), 3.36 (dd, J=4.4, 9.8 Hz, 1H), 3.64 (mn, 1H), WO 99/06397 PCr/US98/15479 00 -418- S 3.76 (in, 1H), 3.79 3H), 3.98 J=9.5 Hz, 1H), 5.93 (in, 2H), 6.77 (d.

Ni J=7.8 Hz, I1H), 6.85 (dd, J=1.7, 8.1 Hz, I1H), 6.93 (mn, 2H), 6.99 J=1.7 Hz, 1H), 7.39 (in, 2H). MS (DCI) W/e 525 Anal calcd for 00 C30H46N206 *0.35 H20: C, 67.86; H, 7.73; N. 5.28. Found: C, 67.87;

H,

7.63; N, 5.11.

Example 452 00 trans. trans-4-(1 .3-Benzodioxol5yfl-2-4iethoxynhenyl)-1 Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 0.87 (dt, J=7 Hz, 3H), 1.15- 1.32 (in, 4H), 3.77 J=2 Hz, 3H), 2.65-5.92 (in, 9H), 5.93 J=4 Hz, 2H), 6.70-6.90 (in, 4H), 7.00-7.45 (mn, 7H). MS (DCI) mle 549 Anal calcd for C31 H33N206 0.4 H20: C, 66.99; H, 6.13; N, 5.04. Found: C, 67.01; H, 6.23; N, 4.68.

Examgle trans. trn!-4-eh hny)4 .3-benzodioxol-5-vIl)l grglN(--nohaoy~mnoehlgroiie i acid The title compound was prepared by the method of Example 418, substituting 2-chlorobenzothiazole for 2-bromopyriinidine. 1 NMR (300 MHz, CDCI3) 8 0.88 J=7Hz, 3H), 1.59 (sextet; J=7Hz, 2H), 2.25- 2.37 (in, I 2.85-2.97 (in, 3H), 3.28-3.36 (mn, 2H), 3.50-3.58 (mn, 3H), 3.60-3.65 (mn, 1 3.67 J=9Hz, 1 H),3.71 3H), 5.87 J=2Hz, 1IH), 5.91 J=2Hz, 1H), 6.57 J=BHz, 1H), 6.73 (dd, J=2Hz, 9Hz, 6.76 J=8 Hz, 2H), 6.91 J=2Hz, 1H), 7.01 J=8Hz, 1H), 7.22 J=8Hz, 7.29 J=BHz, 2H), 7.40 J=7Hz, 1H), 7.55 J=7Hz, 1H).

Example 454 transtrans-2-(2-Ethoxvethyl- 4 butyflaminocarb~nVyinethyl-1pyrrlidne3carboxylic -aid Using the procedures described in Example 1, the title compound was prepared. 1 H NMVR (CDCI3, 300 MHz) 8 0.91 J 7.4 Hz, 3H), 0.94 J 7.4 Hz, 1.19 J 7.0 Hz, 3H), 1.24-1.38 (in, 5H), 1.46-1.60 (in. 4H), 2.03-2.12 (mn, 2H), 3.07 J 8.0 Hz, 1 3.07-3.34 (in, 6H), WO 99/06397 PCT/US98/15479 00 -419- 3.43-3.52 (in, 3H), 3.59-3.74 (in, 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, I1H). 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.

00 ~trans, trans.!2-(4-Methoxy-3.fluoronhenyl- 4 -(l.3-bezdO~-Y) 1-f2-(N-oropyl-N-(2-(moroholin- 4 00 vy1ethyfl)sulf ofyl aiiO tylDrrolidine3carboxylic acid N 10i Ethyl 2 4 methoxY-3f luo roPhen yl)4(13benzodi 1 N-p ropyl-N-[2-vinYlsulf onyl] amino)et hYlpyrroli dine- 3carboxylic acid, prepared. by the procedures of Example 125, was reacted with excess inorpholine for 4 hours at room temperature.

Chromatography on silica gel eluting with EtOAc gave a 65% yield of an intermediate ethyl ester which was hydrolyzed to the title compound with NaOH in ethanol/water. 1II NMR (300 MHz, CDC13) 8 0.81 J=7Hz, 3H), 1.46 (sextet, J=7Hz, 2H), 2.43-2.52 (mn, 4H). 2.70-2.92 (mn, 2.97-3.33 (mn, 6H), 3.60 (dd, J=3Hz, 9Hz, 1H), 3.51-3.59 (in, 1H), 3.62- 3.70 (in, 5H), 3.88 3H), 5.95 2H), 6.72 J=8Hz, I1H), 6.70 (dd, J=2Hz, 8Hz, I1H), 6.90 J=9Hz, 1 6.96 J=2Hz, 1 7.10 J=8Hz, 1H), 7.18 (dd, J=2Hz, 12H1z, 1H).

trans-.trans-2.(3.Fluorg-4-methoxyohenyl- 4 -(l.3-befzodiooxoLS,-Yl- 1 -r2-(N-grop~yl-N-(( 2 .2.2trif Iuoro eth oxyeth ang'~suIto nyfLn mnoCthylPyrrol idin 3c rboxYlIc Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 95-96 O0. 1H NMR (CD3OD, 300MHz) 8 0.80 J=7Hz, 3H), 1.35-1.48 (in, 2H),3.07 (sextet, J=7Hz, 2H), 3.23-3.55 (mn, 8H), 3.80-3.87 (mn, 2H), 3.93 3H 3.94- 4.02 (mn, 4H), 4.66 J=l2Hz, 1H), 5.96 2H), 6.83 J=BHz, 1H), 6.94 J=8Hz, 1H),7.06 J=2Hz, 7.23 J=9Hz, 1H), 7.43 J=9Hz, 1H), 7.49 (dd, J=2Hz,J=12Hz, 1H). MS (DCI/NH3) Wle 635 WO 99/06397 PCT/US98/15479 00 -420trans. trans-4-(l .3-Benzodioxl5yl2-(4-fluororhenytl) -(N-butyl- 00 Using the procedures described in Example 1, the title compound i was prepared. I H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (in, 4H), 2.31 3H), 2.65-2.80 (in, 3.19 J=7 Hz, 1 3.25 N- J=10 Hz, 1H), 3.35-3.65 (in, 4H), 3.79 J=10 Hz, IH), 5.93 2H), 00 6.74 J=7 Hz, 1H), 6.80-6.90 (in, 3H), 6.91-7.09 (mn, 3H), 7.10-7.35 (in, 4H). MS (DCI) Wne 533 (M+H) 4 Anal calcd for C 3 1 H33N205F: C, 69.91; H, 6.25; N, 5.26. Found: C, 69.56; H, 6.26; N, 5.23.

Example 458 trans. trans-2-(3-Fluoro-4-methoxynhenyl)- 4 -(l.3benzodi Using the procedures described in Example 66, the title compound was prepared. 1 NMR (CD3OD, 300 MHz) 8 0.94 (in, 3H), 1.23 (hex, 2H, 1.69 (in, 2H), 3.08 (in,2H), 3.20 3.3-3.5 (mn, 10H), 3.77 (mn, 2H), 3.92 3H), 4.60 (mn, 5.96 6.81 1H, 6.88 (dd, .0 11-, J=2, 6.99 11H, 7.22 1H-, 7.38 (in, 2H). MS (APCI) in/e 581 Anal calcd for C 2 8H37N2O8FS 1.1 TFA: C, 51.37;

H,

5.44: N. 3.97. Found: C, 51.27; H, 5.35; N, 4.11.

ExamaAU trans.. trans2(3FlUoro-4iethxypheny-l 4 -(1.3benzodiox~oI-5-yD- Using the procedures described in Example 66, the title compound was prepared and isolated as a white solid. m.p. 77-78 -IC. I NMVIR (CDCI3, 300MHz) 8 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, 1H), 2.62-2.78 (mn, 3H), 2.85-2.95 (in, 2.97-3.10 3.15-3.35 (mn, 2H), 3.43 (dd, J=3Hz. J=9Hz, 1H), 3.53-3.62 3.66 J=9Hz, 1H), 3.88 3H), 5.95 2H), 6.74 J=8Hz, 1H), 6.82 (dd, J=2Hz, J=8Hz, 6.92 (t, J=8Hz, 111), 6.97 J=2Hz, 1H), 7.12- J=9Hz, 11H), 7.18 (dd, J=2Hz, .1=12H-z. 11H1. MS (DCI/NH3) m/e 565 WO 99/06397 PCT/US98/15479 00 -421trans, trans-!4-(1 .3-Benzodioxol-5.yfl-2-(4-metho-xypheflyl)-1 b utyI-N-(4-nitro benzyfl)aminoIca rbolfm ethyfl yrrol dine-3- 00.

carboxylic acdd Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13 8 (rotamer) 8.11 (2H, m),7.32 00 (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, in), 5.99 (5.97) (2H, d, 5.02 (4.18) (1H, d, J=15), 4.63 (4.38) (1H, d, J=15), 3.79 (3.77) (31-r 3.72 (1H, d, 3.61 (1H, mn), 3.48 (1H, bd, J=15), 3.43-3.20 (2H, in), 3.06 (2H, mn), 2.90 (1H, mn), 3.79 (1H, bd, J=14), 1.43 (1H, in), 1.23 (2H, in), 1.02 (1H, in), 0.84 (0.78) (3H, t, MS (DCI/NH3) Wne 590 Anal calcd for C32H35N308: C, 65.18; H, 5.98; N, 7.13. Found: C, 65.89; H, 5.85; N, 6.85.

Exsmple 46 trans, trans-2-(4- Ethylph enyl)-4-(3 .4-diflIuorop~henyfl- 1 N-di(nbutyl)aminocarbonylmethyl)-Dyrrolidine-3-carboxylic acid 0 Using the procedures described in Example 1, the title compound was prepared. I1 NMR (CD300, 300 MHz) 5 0.78 3H, 0.87 3H.

1.02 (hex, 2H, 1.22 3H, 1.27 (in, 2H), 1.45 (in, 2H, 2.63 2H, 2.77 1H, J=14), 2.94 (dd, 1H, J=7, 3.05 (mn, 3H), 3.3-3.5 in, 3H), 3.44 1H, J=14), 3.66 (in, 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 (DCI/NH3) Wne 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.

ExamrlC 46 trans, trans-4-(l .3Benzodioxol-5-yfl-2-(4-mfethoxyphenyl)? 1 buy--4fur--ehlhnlaiogbnlehlproiie 3-carboxylic acid Using the procedures described in Example 1, the title compound 36 was prepared. 1 H NMR (300 MHz, CD3O1D) 8 0.87 J=7 Hz, 3H), 1.20- 1.50 (mn, 4H), 2.21 J=2 Hz, 3H), 2.64 J=14 Hz, 1H), 2.75 (dd, WO 99/06397 WO 9906397PCT/US98/I 5479 -422- Hz, 1H), 3.05 J=7 Hz, IH), 3.25 J=15 Hz, 1H), 3.35-3.70 (in, 3.77 3H), 5.92 2H), 6.70-6.92 (in, 6H), 6.96-7.10 (in, 4H). MS (DCI) mWe 563 Anal calcd for C 3 2H35N206F -0.5 H20: C. 67.24; H, 6.35; N, 4.90. Found: C, 67.16; H, 6.06; N, 4.81.

ExanAe 46 trans. trans-4-(l.-3no~xl5y)--4mtoyley) 1 butyl-N- 3 -i so 12ropyflphpnylaino)carb onvlmethyl)py rroti dne- 3 00 00 i 3 Using the procedures described in Example'1, the title compound was prepared. I HNMR (300 MHz,* CD3QD) 8 0.87 1.17 J=7 Hz, 6H), 1.20-1.50 (in, 4H), 2.63 J=15 Hz, 1H), 2.75 J=7 Hz, 1H1), 2.85 (in, 1H), 3.00 J=7 Hz, 3.25 J=15 Hz, IH), 3.40-3.70 (in, 3.75 3H), 5.90 2H), 6.65-6.80 (mn, 3H), 6.71 (dt, J=7 Hz, 3H), 7.07 (mn, 3H), 7.20-7.35 (in, 2H). MS (DCl) in/e 573 Anal calcd for C34H40N206 -0.15 H3P04: C, 69.52; H, 6.94; N, 4.77. Found: C, 63.31 H. 6.72: N, 4.43.

E xam p!le -464 trans, trans-!4-( 1.

3 Benzodioxol5.yl-2(4methoxyp I nyl)l butyl- 3- ethylph eny.1) am inocarbonlmlethyl) 12yrroli dine3carb oxylic acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 8 0.87 (in, 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 (in, 2H), 3.13 J=7 Hz, 1 3.20-4.5 (in, 6H), 3.78 3.83 J=8 Hz, I1H), 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, 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.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -423c-i trans. trans-4 1.3-Benzodioxo-5-yI)-2-(4-ethylphelyl)-1-(((N-(3chlo rocphenyl)-N-butyl amino) carbonylmethyl) yrrlidile-3-carboxylic 00 Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDC13) 5 0.87 3H, J=7Hz), 1.23 (t, 3H, J=7Hz), 1.28 (in, 2H), 1.41 (mn, 2H), 2.63 2H, J=7Hz), 2.67 (in, I1H), 00 2.92 (in, 1 3.20 (in, 2H), 3.42 (in, 1 3.60 2H, J=7Hz), 3.93 (in, 1 5.92 2H), 6.75 1 H, J=8Hz), 6.84 (in, 3H), 6.95 (br s, I1H), 7.02 0 1H), 7.10 (br s, 3H), 7.25 (mn, 2H). MSl (APCI) 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.

Examle46 trans, trans-4-( 1.4- Ben zod io xan-6-yfl)-2-(4 -ethylflh enlyl)- 1 chloroohenyl)-N-butylamino~carbonyl)nethyflDgrrolidine-3-carboxyl~ic Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDCI3) 8 0.86 3H, J=7Hz), 1.23 (t, 203H, J=7Hz), 1.25 (in, 2H), 1.40 (mn, 2H), 2.64 2H, J=7Hz), 2.70 (in, 1IH), 2.95 (in, 1 3.20 (in, 2H), 3.40 (in, 1 3.57 (in, 3H), 3.90 (in, 1 H), 4.25 4H), 6.80 I1H, J=8Hz), 6.95 1 H, J=2Hz), 6.95 (in, 2H), 7.07 (br 7.22 (mn, 3H). MS (APCI) Wne 577. Anal. calc'd for C33H37N205CI 0.85 H20: C, 66.90; H, 6.58; N, 4.73. Found: C, 66.92; H, 6.25; N, 4.36.

Example 67 trans. trpns-4- (Ben zof uran- 5-yfl-2 thylp herlyl) 1 chl orophenyl)-N-butyl amino) carbonyflinethyflpyrrolidine-3carboxylic &i Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 0.85 3H, J=7Hz), 1.26 (t, 31-, J=7Hz), 1.30 (mn, 2H), 1.40 (in, 2H), 2.60 2H, J=7Hz), 2.72 (mn, 1IH), 2.93 (mn, I1H), 3.22 (in, 2H), 3.50 (in, I1H), 3.55 (mn, 2H), 3.75 (mn, 1 3.90 (br d, 1 6.75 1 H, J= 1 Hz), 6.80 (br d, 1 6.95 (br s, 1 7.08 (in, 4H). 7.20 1H, J=8Hz), 7.28 1H, J=8Hz), 7.42 (mn, 2H), 7.58 1H, 2 WO 99/06397 PCT/US98/1 5479 00 -424- J=1 Hz), 7.63 1 MS (APCI) rn/ 559 Anal. calc'd for NI

C

33 H35N2O4Cb 0.45 H20: C, 69.88; H, 6.38; N, 4.94. F ound: C, 69.83;

H,

6.04; N, 4.87.

00 Example 468 tran-s-.trans-2-(4-Methoxy-3fuoroghenyl-4-(7-mthoxy-I -3- 4 .NbtylN-Phelamng~ethyllnyrrolidine- 3 00 0 ~Ethyl 2 4 -methoxy-3-fluorophenyl)-4(h-methoxy-1 .3benzodioxol'S-yl)Ij 2 romoeth yl1-pyrrolid ife 3carboxyl 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 diisopropylethylamifle to give the ethyl ester. The ester was hydroyzed with sodium hydroxide to give 148 mg of the title compound as a white powder. I H NMR (300 MHz, CDC13) 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, 3.12-3.22 (in, 2H), 3.30-3.44 (in, 3H), 3.45-3.55 (in, 1 3.62 J=9Hz, 1 3.83 3H), 3.90 3H), 5.95 2H), 6.51 J=7Hz, 2H), 6.55-6.62 (in, 211), 6.69 J=2Hz, 1H1), 6.84 J=BHz, to 1H), 7.02-7.15 (in, 3H), 7.19 (dcl, J=2Hz, 12H-z, 1H).

Example 469 trans. trans-4-(l 4 Senzodio an6yl-2(4-ethylphenyvl di(n-butyflain icgrbnylm thyl)- rrolidine 3 cargyl acid Using the procedures described in Example 1, the title compound was prepared. 1 NMR (300 MHz, CDC13) 8 0.78 3H, J=7H-z), 0.88 (t, 3H, J=7H-z), 1.05 2H, J=7H-z), 1.23 3H, J=7H-z), 1.28 (mn, 2H), 1.45 (in, 2H), 2.64 2H, J=7Hz), 2.78 (mn, 111), 2.9-3.2 (envelope, 4H1), 3.30 (mn, I1H), 3.40 (in, 3.60 (mn, 1 3.80 (mn, 1 4.25 6.80 (d, 1H, J=8Hz), 6.90 (mn, 1H), 6.98 I H, J=2Hz), 7.17 2H, J=8H1z), 7.30 (in, 2H). MS (APCI) in/ 523 Anal. calc'd for C31 H42N205 -1 .1 HOAc: C, 67.73; H, 7.94; N, 4.76. Found: C, 67.81; H, 4.48.

WO 99/06397 PCT/US98/15479 00 Cg-425- Examle 470Z CI trans. trans-4-(1.4-Benzodioxan-6-l-2-(4-methOXVDhenyl-1 butvi-N-(3-methylhenviaminolcarbonvl~methyllovrrolidine-3- 00carboxvic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD30D) 8 0.87 J=7.1 Hz, 3H), 1.30 0 N 2H), 1.44 2H), 2.30 3H), 2.80 J=15.2 Hz, 1H), 2.85 J=9.3 00 Hz, 1H), 3.19 J=9.3 Hz, 1H), 3.33 J=10.2 Hz, 1H), 3.42-3.61 (m, 3H), 3.79 3H), 3.91 J=9.8 Hz, 1H), 4.22 4H), 6.75-6.86 6H), 6.95 J=2.0 Hz, 1H), 7.09 J=8.8 Hz, 2H), 7.22 J=10.2 Hz, 1H), 7.26 J=7.6 Hz, 1H). MS (DCI) m/e 559 Anal calcd for C33H38N206 0.4 CH3C02C2H5: C, 69.97; H, 6.99; N, 4.72. Found:

C,

0.06; H, 6.66; N, 4.48.

Example 471 trans.trans-4-(l 4 -Benzodioxan-6-vl-2-(4-methoxyhenyl---((Nbutvi-N-(3-chlorOphe~nviaminolcarbonvilme~thyllgpyrrolidine-3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD30D) 5 0.87 J=7.0 Hz, 3H), 1.25 2H), 1.40 2H), 2.78 J=14.6 Hz, 1H), 2.86 J=9.0 Hz, 1H), 3.16 J=9.5 Hz, 1H), 3.34-3.43 2H), 3.48-3.62 3H), 3.79 (s, 3H), 3.85 J=9.5 Hz, 1H), 4.22 4H), 6.78 J=8.5 Hz, 1H), 6.81- 6.86 3H), 6.93-7.09 5H), 7.33-7.38 2H). MS (DCI) m/e 579 Anal calcd for C 3 2H35CIN206 1.1 CH3CO2C2H5 0.15 H3P04: C, 63.30; H, 6.46; N, 4.06. Found: C, 63.54; H, 6.09; N, 3.98.

Example 472 trans.trans-4-( 3 -Benzodioxol-5-vl)-2(4-methoxynhenyl) ovridylmethyl)pyDvrrlidine-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 2.84 J=9.6 Hz, 1H), 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 1H), 3.78 3H), 3.81 (mn, 2H), 5.92 2H), 6.73 J=8.1 Hz, 1H), 6.82 (dd, J=1.8, 8.1 Hz, 1H), 6.93 2H), 6.95 J=1.5 Hz, IH), 7.43 4H). 8.44 J=5.2 Hz. 2H). MS (DCI) m/e 433 Anal WO "/06397 PCT/US99/15479 00 -426- S calcd for C25H24N205 -0.3 CH3CO2C2HS: C, 68.57; H, 5.80; N, 6.10.

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

Examnle 47 00 trans trans-4-(1I.3-Benzodioxol-5-yfl)2-(4-methoxylihenl)l butyl- 3-tgert-butylohenylamno~carboylfmethyItIDyrrolidine- 3 00bxyi ai 00 Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.88 J=7.2 Hz, 3H), 1.23 0 9H), 1.26-1.45 (in, 4H), 2.74 (dd, J=15.1 Hz, 1H), 2.84 (mn, 1H), 3.13 J=9.0 Hz, 1H), 3.29 J=15.1 Hz, 1H), 3.50-3.66 (in, 4H), 3.77 3H), 3.84 J=9.6 Hz, 1H),.5.92 2H), 6.74 J=7.7 Hz, 1H), 6.79-6.85 (mn, 4H), 6.86-6.90 (in, 1H), 6.99 J=1.8 Hz, 1H), 7.06 J=1.8 Hz, 1H), 7.13 (in, 2H), 7.33 J=7.7 Hz, 1 7.42 (in, 1 MS (DCI) mle 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.56; H, 7.33; N, 4.69.

Example474 trans, trans-4-( 1.3-Benzodioxol.5-yfl-2-(4-inethoxyphenvi)-I !0btl ltlpey m n)cro l ehlprgidne3 carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CD3OD) 8 0.88 J=7.3 Hz, 3H), 0.92 J=7.3 Hz, 3H), 1.23-1.59 (in, 8H), 2.58 J=7.6 Hz, 2H), 2.75 J=15.3 Hz, 1H), 2.80 (dd, J=8.5, 9.5 Hz, 1H), 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 (in, 3H), 3.78 3H), 3.83 J=9.8 Hz, 1H), 5.92 2H), 6.74 J=8.1 Hz, 1H), 6.79- 6.87 (in, 4H), 7.05 J=1.7 Hz, 1H), 7.10 J=8.8 Hz, 2H), 7.20 (d, 7.8H), 7.29 J=7.6 Hz, 1H). MVS (DCI) m/e 587 Anal calcd for C35H42N206: C, 71.65; H, 7.22; N, 4.77. Found: C, 71.33; H, 7.28; N, 4.74.

WO 99/06397 PCT/US99/15479 00 -427- ExaMale 475 trans, trans-4-(3.4-Dif I uorohenyl-2(4-ethylphenyl)- -(N-(n-butyfl- N 3 -rnethyl Phelfl ami n ocarbonylmethyl) pyrrolidine-3carboxy i c acid Using the procedures described in Example 1, the title compound 005 was prepared. 11H NMR (CD3OD, 300 MHz) 8 0.87 3H, 1.19 31H, 1.28 (in, 2H), 1.43 (mn, 2H), 2.28 3H), 2.60 2H-, 2.66 (in, 2H), 3.06 (in, 3.21 1H. J=15), 3.42 (dd, 1H, 3.58 (in, 3H).

00 3.71 I1H, 6.80 2H), 7.06 4H), 7.18 (in, 4H), 7.45 (in, 1 H).

MS (APCI) mn/e 535 Anal calcd for C32H36N2O3F2 1.3 HOAc: C, 67.83; H, 6.78; N, 4.57. Found: C, 67.83; H, 6.46; N, 4.70.

-trans. trans-2-(4-EthylPhenyl4( 3 .4-difluoropohenl)fl1-(N-( n-butyfl- N- 3 chi oroph enyfl) in ocarbonyl mpthyl~~pyrrolidi ne3carboxy.Lic acid Using the procedures described in Example 1, the title compound was prepared.

I

1 H NMR (CD3OD, 300 MHz) S 0.82 3H, 1.16 31H.

1.23 (in, 2H), 1.35 (in, 2H), 2.55 2H. 2.66 (in, 3.01 (t.

1H, 3.16 1H, J=15), 3.32 (dd, 1H, 3.56 (in, 3H), 3.67 (d, 1 H, 6.94 I1H, 7.02 (in, 51H), 7.14 (in, 2H), 7.32 (in, 31H). MS (APCI) Wne 555 Anal calcd for C 3 1 H33N203C1F2 0.6 TFA: C, 61.88; H, 5.42; N, 4.48. Found: C, 61.90; H, 5.62; N, 3.98.

ExaMple 477 trans. trans-4-(l.4 Be g gh y) -btityl- N- Q -chi o rohenyl)ai nocarbg nyl mgthvl pyrrol d ine3-carboxyli c -acid Using the procedures described in Example 1, the title compound was prepared. 1H NMR (300 MHz, CD3OD) 8 0.87 J=7 Hz, 31H), 1.10- 1.30 (mn, 4H1), 2.60-2.75 (in, 2H), 3.03 J=7 Hz, 1H1), 3.15-3.75 (mn, 6H-), 4.02 (mn; 4H), 6.75 J=6 Hz, 1H), 6.85 (dd, J=7 Hz, 1H), 6.90 (7.19, Jin Hz, 61H), 7.32-7.43 (in, 31H). MS (DCI) in/e 567 Anal calcd for 031 H32N205FCI 1.6 H20: C, 62.49; H, 5.95; N, 4.70. Found: C, 62.20; H. 5.54; N, 4.42.

WO 99/06397 PCT/US99/15479 00 -428citrans. trans-4-(Benzof uranl5y)--(4-ethyl phe nl)l I -N-di (nbutyl~amInocarbolylmethyl)-yrrolidifle-3carboxylic acid 00 Using the procedures described in Example 1, the title compound was prepared. 1 HNMR (300 MHz, CDCI3) 8 0.78 3H, J=7Hz), 0.84 (t, 3H, J=7Hz), 1.05 2H, J=7Hz), 1.21 3H, J=7Hz), 1.25 (in, 2H), 1.45 (in, 2H), 2.62 2H, J=7Hz), 2.80 I1H, J=1l3Hz), 3.0 (in, 2H), 3.15 (mn, 00 2H), 3.35 (in, 1 3.43 (in, 2H), 3.52 (in, I1H), 4.40 (in, 2H), 6.73 I1H, J=lHz), 7.14 2H, J=BHz), 7.26 1H), 7.31 2H, J=BHz), 7.44 (s, 0 2H), 7.60 I1H, J=1 Hz), 7.65 I MS (APOI) iii/e 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.

s trans. trans-2-(4-Methoxy-3-flugrophefYl)4(7methoxy-l .3benzodioxoli-5-yl)l-r~2-(N-rool-N-(D2yrrolidifleca rbonylm ethyl)am i no'ethyllpyrrol idi ne3ca rbo xylic acid Ethyl 2-4mtoy3furphnl -7mtoy13benzodioxol-5-yl)-l1-[2-( N-propyl-aminoethyl]-PYrrOlidifle- 3 0 carboxylate, prepared according to the procedures of Example 61 B (300 mg), N-bromoacetyl pyrrrolidine (132 mg) and diisopropylethylamfifle (154 mng) 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 1 D. I1 NMR (300 MHz, CDCI3) 8 0.88 J=7Hz, 3H), 1.30-1.45 (in, 2H), 1.75-1.92 4H), 2.30-2.40 (mn, I1H), 2.47-2.58 (in, 2H), 2.70-3.00 (in, 5H), 3.24-3.45 (in, 6H), 3.50-3.70 (in, 2H), 3.83 3H), 3.86 J=9Hz, 1H), 3.88 3H), 5.93 2H), 6.58 (d, J=2Hz, 1 6.70 J=2Hz, I1H), 6.87 J=8Hz, 1 7. 10 J=9Hz, 1 H).

7.21 (dd, J=2Hz, 12Hz, 1H).

Examogle 480 trans, trpns-2-(4-Methoxylheflyfl- 4 1.3-benzodioxol-5-yl)-1 (p2erhydro e I ycarbo nyl(D1e ucyl) aino) ethyl) pyrroidine- WO 99/06397 PCT/US98/15479 00 S-429- Example 480A SD-Leucine O-benzvl 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 0 5 reaction was warmed to reflux with removal of water overnight. Once TLC indicated consumption of starting material, the reaction was Scooled, and the resulting solid was filtered and washed with EtOAc to oo give the title compound as a white powder (14.26 g, 99%).

Example 480B N-Perhydroazeoinvlcarbonvl-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 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 h H3P04 (2 x 20 mL), and brine (20 mL), dried over Na2SO4, decanted and evaporated. The residue was purified by flash chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a crystalline solid (0.835 g, 89%).

Example 480C N-Perhvdroazepinylcarbonvl-D-Leucine To the compound resulting from Example 480B (200 mg) dissolved in dry ethanol (1.0 mL) was added 10% palladium on carbon (10 mg).

After flushing the flask with nitrogen, the reaction was stirred vigorously under an atmosphere of hydrogen for 1 hour. The reaction was filtered through infusorial earth and evaporated to give the title compound (140 mg).

WO 99/06397 PCT/US98/15479 -430- C Example 480D l trans, trans-2-(4-MethoxvDhenvl-4-( 1.3-benzodioxol-5-vl)-1 (cyanomethvl)-Dvrrolidine-3-carboxvlic acid ethyl ester To the compound resulting from Example 1C (510 mg of a 50 wt.

5 solution in toluene) dissolved in acetonitrile (2.0 mL) was added diisopropylethylamine (0.24 mL), followed by bromoacetonitrile (0.072 N mL). After 2 hours, TLC indicated complete comsumption of starting 00 material. The solvent was evaporated, and the residue was purified by O flash chromatography on silica gel eluting with 20 40% EtOAc in o0 hexanes to give the title compound as a coloress"oil (0.28 g, 99%).

Example 480E trans.trans-2-(4-MethoxvDhenvl)-4-(1,3-benzodioxol-5-vl)-1 aminoethyl)-Dyrrolidine-3-carboxvlic acid ethyl ester s1 To the compound resulting from Example 480D (275 mg) dissolved in 10 mL each of triethylamine and ethanol was added Raney nickel catalyst (0.2 and the reaction was placed under a hydrogen atmosphere (4 atmospheres) for 3 days. The reaction was filtered and evaporated. The residue was dissolved in methylene chloride (10 mL) and extracted with 1 M HCI (5 x 1 mL). The combined aqueous extracts were basified and then extracted with methylene chloride (5 x 2 mL).

The combined organic extracts were dried with MgSO4, filtered and evaporated to give the title compound as an unstable oil (0.14 g).

Example 480F trans, trans-2-(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-yl)-1 (Derhydroazeinhylcarbonyl)leucvl)amino)ethyl)-prrolidine-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 WO 99/06397 PCT/US98/15479 00 -431f lash 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 48O 00 5 trans, trans-2-(4-Methoxyphenl)- 4 -(l.3-benzodioxol-5-yl)-1 (12erhydroazelinylcarbonylleucflamiflo)ethyl)pyrrolidine3carboxylic 00 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 1 0 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 3. 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 fractions. I H NMR (CDCI3, 300 MHz) 8 0.82 (dd, 6.4, 4.4 Hz, 6H), 0.87 (dd, J 5.7, 5.7 Hz, 6H), 1.04-1.28 (in, 3H), 1.34-1.65 (in, 19H), 2.95 (br m, 2H), 3.15-3.40 (mn, 14H), 3.40-3.55 (in, 4H), 3.58-3.68 (mn, 2H), 3.70- 3.76 (br m, 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), 8.2 (br s. 1 8.5 (br s, I1H). MS(DCI/NH3) in/e 623 Anal calcd for C34H46N407 2.00 TFA: C, 53.65; H, 5.69; N, 6.58. Found: C, 53.66; H, 5.66; N, 6.54.

Example 48 trans, trans-4-(1.3Bnoixl -l--4mthxpey). di(rn-hexyflaminocarbonlmlethyflDprrolidine 3 carboxylic -acid Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 5 0.80-0.95 (in, 6H), 1.0 (in, 2H), 1.07 (1.55, J=m Hz, 14H), 2.70 J=13 Hz, 1H), 2.85-3.15 (mn, 4H), 3.20-3.60 (in, 3.64 J=10 Hz, 1H), 3.79 3H), 5.90 (mn, 2H), 6.70 8H), 1, 6.80-6.93 (mn, 3H), 7.05 1H), 7.35 J=10 Hz, 2H). Anal WO 99/06397 PCT/US98/15479 00 -432calcd for C 3 3H46N206 -1.7 H20: C, 66.35; H, 8.34; N, 4.69. Found:

C,

66.32; H, 8.04; N, 4.52.

00 xmi48 trans, trans-4-( 4 Bnzodi oxa-6Y)2(4-fluoroghenyl-1-N-butyI

N-(

3 -methyinheflyt)aminocronyl m ethyl gyrriaine-3ca boacid 00 Using the procedures described in Example 1, the title compound was prepared. 1 NMR (300 MHz, CD300) 8 0.87 J=7 Hz, 3H1), 1.20- 1.35 (in, 2H), 1.35-1.40 (in, 2H), 2.32 3H),'2.5.5-2.70 (mn, 2H), 2.97 (t, 0 J=7 Hz, 1H), 3.22 J=14 Hz, 1H), 3.25-3.70 (in, 5H), 4.20 (in, 6.97 J=2 Hz, 1 7.09 (in, 2H), 7.15-7.35 (in, 2H). MS (DCI) W/e 547 Anal calcd for C 3 2H35N205F 1.2 H20: C, 67.64; H, 6.63;

N,

4.93. Found: C, 67.73;, H, 6.37; N, 4.70.

transtrpfl--(l 3 enzodioxol-5il2(4melhoxyphenyIl Using the procedures described inl Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13 6 (rotamer) 8.14 (2H, mn), 8.05 (7.83) (1H1, in), 7.60-7.30 (3H, in), 7.13 mn), 7.10-6.70 (5H, mn), 5.94 (2H, in), 5.43 (5.33) (IH1, d, J=12), 4.75 (1H, bd, J=15), 4.60-4.20 (2H, in), 4.10 (2H, in), 3.80 (3 .76) (3H, 3.75-3.40 (3H, in), 3.20-2.80 (2H, mn), 1.50 (1H, mn), 1.30 (1H, mn), 1.20-1.00 (211, in), 0.91 (0.78) (3H1, t' MS (DCI/NH3) in/e 590 Anal calcd for C32H135N308 2.1 TEA: C, 52.44; H, 4.51; N, 5.07. Found: C, 52.25; H, 4.83; N, 5.71.

Exa-mple 484 trn~rans- 4 1- 2 Dihydrh nfrpfl-9;.vj thI' n 1 buv--34d ~lD--bny~mnocroy~ghlproiincarboxylic acid Using the procedures described inl Example 1, the title compound was prepared. I H (300MHz, CDC13 8 (rotamer) 7.40 (2H1, in), 7.30-7.10 (4H, in), 6.90-6.70 (3H, in), 6.48 (1 H, in), 5.45 (111, in), 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 (1H, in), 3.8 ko I o s, Ca, f~ (2H. t. J1I0). 2.90 (1 H.

WO 99/06397 PCT/US98/15479 00 -433m 2.64 (2H, q, 1.52 (1H. in), 1.31 (2H, in), 1.22 (3H, dt, J=9, 2), 1.07 (1 H, in), 0.92 (0.78) (3H, t, MS (DCI/NH3) mle 601 (M+H 4 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.

00 _Example 48 trans. trans-4-(1 .3.Benzodioxol-5-yl)I-2-(4-methoxylheflyfl-1 00 butyl-N-(4-hegtyflamino~carbolylnethyflDyrrolidine-3-carboxylCG Using the procedures described in Example 1, the title compound was prepared. IH NMR (300 MHz, CD3OD) 6 0.71-1.04 (in, 11H), 1.07- 1.35 (in, 6H), 1.73-1.53 (mn, 4H), 2.79-3.25 (in, 5H), 3.35-3.44 (mn, 1IH), 3.51-3.68 (in, 3H), 3.78-3.89 (in, 1IH), 3.79 3H), 5.92 (mn, 2H), 6.74 (dd, J=1.7, 8.1 Hz, I1H), 6.85 (td, J=1.7, 8.1 Hz, 1 6.93 (in, 2H), 7.02 (dd, J=1.7, 9.5 Hz, 1 7.36 (in, 2H). MS Wne 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 -Methylcyclohexyfl-4- (1 benzodio xol 1 -N di(n-butyflaiinocarboflylinethyfl)Dyrrolidile-3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.88 (3H, d, J 7Hz), 0.92 (3H, t, J 7Hz), 0.96 (3H, t, J 7Hz), 1.05 (1H, mn), 1.22-1.40 (7H, in), 1.45-1.65 (6H, in), 1.67-1.84 (4H, mn), 3.17-3.45 (6H, in), 3.70 H, bin), 3.82 (1 H, dd, J 9Hz, 15Hz), 3.86 (1H, d, J 15Hz), 5.93 (2H, 6.73 (1 H. d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MS (DCI/NH3) m/e 501 Anal calcd for C29H44N205 0.25 CF3CO2H 66.96; H, 8.43; N, 5.29. Found: C, 66.79; H, 8.60; N, 4.87.

WO 99/06397 PCT/US98/15479 00 -434- Eamn~lA 48 trans, trans-2-(2-Propyloentyfl-4-( 1.3-benzodioxol-5-yfl-I N-di(nbutyliaminocarbonylmethyl-yrrolidile-3-carboxlic acid Using the procedures described in Example 1, the title compound 00 was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.12- 1.40 (13H, in), 1.42-1.68 (6H, in), 2.90 (1H, mn), 3.14-3.30 (2H, in), 3.33 00 (4H, in), 3.72 (1H, brrn), 3.90 (1H, brm), 5.93 (2H1, dd, J 2Hz, 4Hz), 6.73 0 d, J 8Hz), 6.78 (1 H. dd, J 2Hz, 8Hz), 6.88 (1 H, d, J 2Hz). MS (DCI/NH3) Wne 517 Anal calcd for C30H48N205 0.35 CF3CO2H: C, 66.24; H, 8.76; N, 5.03. Found: C, 66.26; H, 8.82; N. 4.98.

trans. trans-4-( 1.4-Benzodioxan-6-yl)I-2-(4-fluorgphenyl)-l -(N.N-di(nbUtflaminocarbonylmethyl-yrrolidine--arboxylic acid Using the procedures described in Example 1, the title compound was* prepared. 1 NMR (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, I1H), 2.95-3.60 (in, 7H), 3.71 J=9 Hz, 1 4.21 4H), 6.72 1 6.91 (dd, J=8 Hz, 1 6.97 J=2 Hz, I1H), 7.05 J=7 Hz, 2H), 7.40-7.50 (in, 2H). MS (DCI) mWe 513 Anal calcd for C29H37N205F -1-2C F3000H: C, 58.07; H, 5.93; N, 4.31. Found: C, 57.94; H, 5.8 1; N, 4.56.

Exam~le48 trans. trans- 2- (3-M ethylIpefltyfl- 4 1.3-benzodi oxol- 5-ylI- 1 N-di (nbutyl)aminocarbolylnethyl)-pyrrolidifle-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 0.83 (3H, t, J 7H-z), 0.85 (3H, d, J= 7H-z), 0.91 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.05-1.22 (2H, in), 1.22-1.41 (7H, mn), 1.43-1.68 in), 1.89 (1 H, in), 2.94 (1 H, t, J 6Hz), 3.15-3.27 (3H, mn), 3.29-3.60 in), 3.72 (1H, brd, J 6Hz), 3.92 (1 H, 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 21-z). MIS (DCI/NH3) m/e 489 Anal calcd for C28H44N205 WO 99/06397 PCT/US98/15479 00 -435- .0.30 CF3CO2H: C. 65.70; H, 8.54; N, 5.36. Found: C, 65.93; H, 8.81; N, (1 4.84.

00Exml49 C 5 trans. trans-2-(2-Ethylbutyfl-4-( 1.3-benzodloxol-5-yfl)-1-(N.N-di(nbutyflaminocarbgnylmethyl)0yrrolidile-3-carboxylic acid (Ni Using the procedures described in Example 1, the title compound 00 ~was prepared and isolated as an amorphous solid. 1H NIMR (CDCI3, 300 MHz) 8 0.85 (6H, in), 0.92 (3H, t, J 7Hz), 0.97 (3H, t, J 7Hz), 1.13- 1.41 (13H, in), 1.43-1.72 (6H, in), 2.96 (1H, brm), 3.12-3.52 (6H, mn), 3.55-3.70 (1H, mn), 3.70-3.86 (2H, mn), 3.99 (1H, brm), 5.93 (2H, dd, J 2Hz, 4Hz), 6.73 (1 H, d, J 8Hz), 6.78 (1H1, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). IMS (DCI/NH3) W/e 489 Anal calcd for C28H44N2O5~ 0.45 CF3002H: C, 64.28; H, 8.30; N, 5.19. Found: C, 64.16; H, 8.38; N, 5.08.

trans. trans- Flu oro-4 -methoxyphenYl- 4 3-benzodioxol carboxylic acid Using the procedures described in Example 66, the title compound was prepared. 1 HNIMR (CD3OD, 300 MHz) 0.74 3H, 0.83 3H, 0.94 3H, 1.44 (hex, 2H), 1.67 (in, 4H), 2.91 2H, J=8), 3.04 (dd, 2H, J=8,10), 3.1-3.6 (in, 5H), 3.78 (mn, 2H), 3.92 3H), 4.60 (mn, I1H), 5.97 2H), 6.82 I H, 6.89 (dd, 1IH, J=2, 7.01 1 H, 7.22 1H, J=9),'7.39 (in, 2H). MS (ESI) mWe 579 trans, trans-2-(4-Methoxy-3-fluorophenyl) 4 -(l.3-ben 1-[-N1rplNf-typrmdnZylmn~tylyr liie3 1 -Dimethylainino-1 -pentene-3-one, prepared by the method described in Syn. Comm. 12 35 (1982), was converted to 2-amino- 4-ethylpyrimidine with guanidine by the method of Chem. Ber. 97, 3397 (1964). This material was converted to 2 -b romo-ethyl -pyrii ndinle with NaNO2 and HBr, using the method of Helv. Chim. Acta 75, 1629 WO 99106397 PCT/US98115479 00 c-I -436- (1992). This bromopyrimidine was reacted with ethyl 2-(4methoxphenyl)-4-(1 ,3-benzodioxol-5-yl)- 1 ropylamino)propylJpyrrolidine-3-carboxylate, prepared using the -procedures of Example 00 61 B, using the procedure for Example 418, to give the title compound as a white powder. 1 H NMR (300 MHz, CDCI3) 8 0.8-3 J=7Hz, 3H), 1.11 (t, J=7Hz, 3H1), 1.45 (sextet, J=7Hz, 2H), 2.18-2.27 (in, IH), 2.45 J=7H1z, 00 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, 8Hz, 1H), 6.82 J=9Hz, 1H), 6.92 J=2Hz, 1H), 7.05 J=9Hz-, 1H), 7.15 (dd, J=2Hz, 12Hz, 1H), 8.10 J=4Hz, 1H).

Example 493 trans. trpns-4-(1.3Bnoix 5y)2-4mtoyhnl- butyl- N-(3 .4-dim ethyl ph enylainoca rbonyfl) ethyl~Dyrro lid ine-3- Using the procedures described in Example 1, 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, 2H1), 2.22 3H1), 2.29 3H), 2.79 (d.

J=14.9 Hz, 1H), 2.84 (dd, J=8.6, 9.7 Hz, 1H), 3.16 J=9.5 Hz, 1H), 3.32 0 J=15.3 Hz, 1H), 3.43-3.61 (in, 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, 111), 7.11 (in, 311). MS mWe 559(MH+). Anal calcd for C33H38N206-0.3H20:

C,

70.27; H, 6.90; N, 4.97. Found: C, 70.24; H, 6.62; N, 4.58.

Examgle 4 tran. trans-2-(a-Meth Llgent-3-en-1 1.3-benzodioxol-5_yflj- (N.N-di(n-butyflaminocarbonflmlethyl-Dyrrolidine3carboxylic acid Using the procedure described in Example 1, the title compound was prepared and isolated as an amorphous solid. 1H NMR (CDCI3, 300 MHz) 6 0.92 (3H. t. J 7Hz), 0.97 t, J 7Hz), 1.22-1.40 (5H, mn), 1.44-1.61 (8H, in), 1.82 (1H, brm), 2.02 (2H, in), 3.05-3.30 (4H, in), 3.3.8 (1H, in), 3.55 (1H, brm), 3.85 (2H, in), 4.12 brd, J 15H1z), 5.11 (1H, dd, J 6Hz, 12Hz), 5.93 (2H, 6.73 (1 H, d, J 8Hz), 6.78 (1 H, dd, J 2Hz, 8Hz), 6.88 (1H, d, J 2Hz). MVS (DCI/NH3) Wle 487 Anal calcd for C28H42N205 0.7 CF3CO2H 62.34; H, 7.60; N, 4.95.

Found: C, 62.49; H, 7.43; N, WO 99/06397 PCT/US98/15479 00 -437- 1 -(N-Phenylamilocarboflylmethyl-2-(4-methoxyPhenvfl-4-(l .3- .be-nzodioxol-5-ylOpYrrolidife3carboxylic acid 00 Eamgle 495A N-Ph enyl br m oacet ami de 00 To a stirred solution of aniline (7.40 mmol) in methylene chloride C) (25 ml) at -50 OC was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl broftde (0.72 mL, 7.40 mmol, I eq) such that the temperature did not exceed -40 0 C. 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 (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 evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.

trans. trans-i 1 (N-Phenylaminocarbonylmthyl-2(4-methoxYphenvjL- 1.

3 benzodolOXl5lIDyrrolidine3cairboxyllc acid Using the procedures described in Example 1 and the compound resulting tram Exampe 495A, the title compound was prepared. 1H NMR (300 MHz, CDCI3) 8 8.8 (bs, 1H) 7.49 (2H, d, J=8Hz), 7.38 (4H, in), 7.11 (1H, tt, J=8&2Hz), 6.99 (1H, d, J=2Hz), 6.91 (2H, d, J=8Hz), 6.86 (1H, d, J=2Hz), 6.81 (1 H, d, J=8Hz), 5.99 (1H, d, J=2Hz), 5.98 (1H, d, J=2Hz), 3.94 (IH, d, J=lOHz), 3.78 (3H, 3.70 (1H, ddd, J=6, 5&3Hz),-3.42 (1H, dd, J=10&3Hz), 3.41 (1H, d, J=l6Hz), .3.18 (1H, dd, J=11&9Hz), 3.01 (1H, t, J=lOHz), 2.93 (1H, d, J=l6Hz). MS (DCl, NH3) m/e 475 Anal. Calc for C27H26N206 1 H20: C, 65.85, H, 5.73, N 5.69, Found: C, 65.95, H, 5.52, N, 5.38.

WO 99/06397 PCT/US98/15479 00 -438citrans, trans- 1 (N Dimethyl nhenyt) am in ocarbonl methyl') -2-(4 methoxyohenyl)-4-( 1.3-benzodioxol-5-ylDyrrolidIfle-3-carboxylic acid Using the procedures described in Example 1, the title compound 00 was prepared. I H NMR (300 MHz, CDC13) 8 8.68 (1 H, bs), 7.64 J=8Hz), 7.38, (2H, d, J=8Hz), 7.09 (1 H, t, J=8Hz), 6.97, (1IH, d. J=8Hz), 6.90 (1 H.

c-i d, J=2Hz), 6.88 d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.76 (1H, d, 00 J=8Hz), 5.97 (OH, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.95 (1H, d, J=lOHz), 3.80 (3H, 3.70 (1H, ddd, J=6, 5&Hz), 3.48'(1H, dd, J=10&3Hz), 3.44 (1H, d, J=l6Hz), 3.18 (IH1. dd, J=11&9Hz), 3.06 (IH, t, J=lOHz), 2.96 (1H, d, J=l6Hz), 2.31 (3H, 2.16 (3H, MS (DCl, NH3) mWe 503 Anal. Calc for C29H30N206 -0.5 H20: C, 68.09, H, 6.11, N. 5.48. Found: C, 68.13, H, 5.91, N, 5.29.

Examgle 49 trans. trans-1 (N-(2.4-Di methylphgnylami nocarbonylm ethyl- 2 -0 4 methoxyphenyfl-4-(1 .3-benzodioxol-5-yl~PYrrolidinfe3-carboxylic acid Using the procedures described in Example 1, the title compound was prepared. I 1 H NMR (300 MHz, CDC13) 8 8.60 (1H, bs), 7.78 (d, J=8H-z), 7.38, (2H, d, J=8H-z), 6.99 (1 H, in), 6.95, (1 H, d, J=8Hz), 6.94 (1H, d, J=2Hz), 6.88 (2H, d, J=8Hz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1 H, d, J=8Hz), 5.97 (1H, d, J=2Hz), 5.96 (1H, d, J=2Hz), 3.92 (1H, d, J=lOHz), 3.79 (3H, 3.68 (1H, ddd, J=6, 5&3Hz), 3.43 (1H, dd, J=1 0&3Hz), 3.42 (1 H, d, J=1l6Hz), 3.18 (1 H, dd, J=1 1&9Hz), 3.04 (1 H, t, J=lOHz), 2.95 (1H, d, J=l6Hz), 2.29 (3H, 2.24 (3H, MS (DCl, NH3) W/e 503 Anal. Calc for .C29H30N206 0.75 H20: C, 67.50, H, 6.15, N 5.43. Found: C, 67.42; H, 5.95; N, 5.13.

trans. trans-i 1 (N-(2.5-Dimethyllhenyl)aminocarbonylmethyl 2 4 methoxylhenyfl-4-(1 .3benzodioxol-5-ylDyrrolidine3carboxylic acid Using the procedures described in Example 1, the title compound was prepared. 1 H NMR (300 MHz, CDC13) 8 8.62 (1H, bs), 7.79 (1H, bs), 7.38, (2H, d, J=8Hz), 7.03 (1H, d, J=BHz), 6.95, (1H, d, J=8Hz), 6.94 d, J=2H-z), 6.88 (2H, d, J=81-Iz), 6.82 (1H, dd, J=8&3Hz), 6.77 (1H, 0=H) .7 (9H. 0) 92 d. J=l OHz), 3.78 (3H, 3.70 (1 H.

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 00 -439ddd, 5&3Hz), 3.48 (1 H, dd, J=1 0&3Hz), 3.42 (1 H, d, J=1l6Hz), 3.18 (I1H, dd, J=1 1&9Hz), 3.04 (1 H. t, J=l OHz), 2.95 (1 H. d, J=l 6Hz), 2.29 (3H, 2.24 (3H, MS (DCI, NH-3) We 503 Anal. Calc for C29H-30N206 0.5 H20: C, 68.09; H, 6.11; N, 5.48. Found: C, 67.72; H, 5.89;, N, 5.25.

E-amglA 49 trans. trans-!I N(3.4- Dim ethylph elyflam ino carbgn l lmethyl- 2 4 methoxygheflyl)-4-(1- 3-benzodioxol1S5-ylyrrolidine3acarboxylic acid Using the procedures described in Example 1, the title compound was prepared. I H NMR (300 MHz, CDCI3) 8 8.73 (1 H, bs), 7.38 (2H, bd, J=8Hz), 7.30, (1H, d, J=3Hz), 7.20 bs), 7.08, d, J=BHz), 7.01 (1H, bs), 6.90 d, J=BHz), 6.85 (1H, bs), 6.80 (11H, d, J=8Hz), 5.99 (1 H, d, J=3Hz), 5.98 (1 H, d, J=3Hz), 3.92 (1 H, d, J=1lOHz), 3.78 (3H, s), 3.70 (1 H, ddd, 5&3Hz), 3.48 (1 H, dd, J=1 0&3Hz), 3.42 (1 H. d.

J=1l6Hz), 3.18 (1 H, dd, J=1 1&9Hz), 3.04 (1 H. t, J=1lOHz), 2.95 (1 H, d.

J=16H-z), 2.25 2.21 (3H. MS (DCI, NH-3) We 503 Anal. Calc for C29H-30N206 0.75 H20: C, 67.50; H, 6.15; N 5.43. Found: C, 67.24; H, 5.94; N, 5.20.

trans. trans-I .5-Dimethylphenl)amiflocarboflylmethYl)- 2 4 methoxyghgnyfl-4-( 1.3benz.odioxoI-S-yl)DYrrolidine3-rarboxylic acid Using the procedures described In Example 1, the title compound was prepared. 1H NMR (300 MHz, CDC13)S88.75 (1H, bs), 7.35, (2H, d, J=8Hz), 7.10 (211, 7 .02 d, J=3Hi). 6.9Q (2H, d, J=8Hz), 6.84 (IH-, d, J=2Hz), 6.80, (IH, d, J=8Hz), 6.76 bs), 5.99 (11-1 d, J=3Hz), 5.98 (0H, d, J=3Hz), 3.92 (1H, d, J=lOHz), 3.79 3.68 (1H, ddd, J-6, 5&3Hz), 3.40 in), 3.18 dd, J=11&9Hz), 2.98 t, J=lOHz), 2.88 d, J=l6Hz), 2.3 MS (DCI, NH-3) We 503 Anal.

Calc for C29H130N2O6 0.5 H20: C, 68.09; H, 6.11; N 5.48. Found: C, 67.93; H, 6.01; N, 5.19.

WO 99/06397 PCT/US98/15479 00

O

C -440- SExample 501 C Alternate Preparation of (+)-trans. trans-1-(N.N-Di(n-butylaminocarbonvlmethyl)-2-(4- 00 methoxvohenyl-4-(1.3-benzodioxol-5-vIDyrrolidine-3-carboxylic acid Hydrochloride Salt Example 501A 00 N. N-Dibutyl bromoacetamide 0 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 °C for 15 minutes.

A solution of 2.5% aqueous H3P04 (500 mL) was slowly introduced, and 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-Nitrovinvl)-1.3-benzodioxole To piperonal (15.55 kg, 103.5 mol) under mechanical stirring and under nitrogen was added ammonium acetate (13.4 kg, 173.8 mol), acetic acid (45.2 kg), and nitromethane (18.4 kg, 301.4 mol) sequentially. The mixture was warmed to 70 After about minutes, the yellow product began to crystallize. The reaction temperature was raised to 80 °C and stirred for about 10 hours until minimal piperonal remains. The somewhat thick reaction mixture was cooled to 10 °C and filtered. The precipitate was washed with acetic acid (2 x 8 kg) and then water (2 x 90 kg). The product was dried under a nitrogen purge and then in a vacuum oven at 50 °C for 2 days to afford 15.94 kg of the title compound as a bright yellow solid.

WO 99/06397 PCT/US98/15479 00 O -441- SExamle 501CI 4-Methoxvbenzovl 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 00 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 00 heated to 60 °C for 8 hours until no 4-methoxyacetophenone was 0 detected by HPLC. The mixture was cooled to 20 OC and quenched by I 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 yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg Example 501D Ethyl 2-(4-methoxybenzoyln-4-nitromethyl-3-(1.3-benzodioxol-5-l o butvrate 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. cis2-(4-methoxvohenvl3-4-(1.3-benzodioxol-5-vl) pyrrolidine-3-carboxvlate Raney nickel (20.0 from which the water had been decanted, was charged to a stirred hydrogenator equipped with a thermocouple.

WO 99/06397 PCr/US98/15479 00

O

C -442- C THF (20 mL), the crude compound resulting from Example 501D (40.82 g, N 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 oo 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 00 and found to contain 13.3 g (75% yield) of the cis, cis-pyrrolidine O compound. The filtrate was concentrated and chased with additional 1 THF (200 mL) to give a final volume of 100 mL. 'he mixture was neutralized with 2 I 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.

1 Example 501F Ethyl trans. trans-2-(4-methoxyphenvyl-4-(1.3-benzodioxol-5-vl) pyrrolidine-3-carboxvlate The solution of the compound resulting from Example 501E (38.1 2 g, 0.103 mol) was chased with ethanol (200 mL) to a final volume of 100 mL and sodium ethoxide (3.40 g, 0.050 mol) was added. The mixture was heated to 75 When HPLC shows of the cis,cis isomer remaining, the mixture was cooled to room temperature. The product was assayed by HPLC against an external standard and found to contain 34.4 g (90% yield) of the title compound. The crude compound solution was concentrated and the residue taken up in isopropyl acetate (400 mL). The organic layer was washed with water (2 x 150 mL) and then extracted with 0.25 M phosphoric acid solution (2 x 400 mL). The combined phosphate layers were stirred with ethyl acetate (200 mL) and neutralized to pH 7 with solid sodium bicarbonate (21 The organic layer was separated and found to contain 32.9 g of the title compound.

WO 99/06397 PCT/US98/15479 00 O -443- ExamDle 501G Ethyl (2R.3R. 4S)-(+1-2-(4-methoxvDhenvl)-4-(1.3-benzodioxol-5-vl pyrrolidine-3-carboxylate. mandelate salt The solution resulting from Example 501F was chased with oo 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 S 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 o00 stirred for 5 hours. The product was filtered and dried in a vacuum N 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-methoxyDhenvl)-4-( .3-benzodioxol-5-vl- 1 di(n-butylaminocarbonvlmethyl)- Dyrrolidine-3-carboxylic acid The compound resulting from Example 501G (20.0 g, 0.0383 mol) was suspended in ethyl acetate (150 mL) and 5% sodium bicarbonate solution (150 mL). The mixture was stirred at room temperature until the salt dissolved and carbon dioxide evolution had ceased. The organic layer was separated and concentrated. The residue was chased with acetonitrile (200 mL) to a final volune of 100 mL and cooled to 10 OC.

Diisopropylethylamine (11.8 mL, 0.0574 mol) and the compound resulting from Example A (10.5 g, 0.0421 mol) were added, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was concentrated and chased with ethanol (200 mL) to a final volume of 100 mL. Sodium hydroxide solution 20 mL, 0.200 mol) was added, and the mixture was heated at 60 °C for 4 hours until HPLC showed no starting material remaining. The reaction mixture was poured into water (400 mL) and washed with hexanes (2 x 50 mL). The aqueous layer was washed with hexane (2 x 20 mL). A stirred mixture of the aqueous layer and ethyl acetate (400 mL) was neutralized to pH 5 with concentrated HCI (12 mL). The organic layer was separated and found to contain 18.3 g (94% yield) of the title compound.

WO 99/06397 PCT/US98/15479 00 0 (CN -444- SExample 5011 (2R.3R.4S4-(+-)2-(4-methoxyphenvyl-4-(1.3-benzodioxol-5-vl-1 oo di(n-butyl)aminocarbonylmethvl)- Dvrrolidine-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 S thermocouple, was added 39.4 mL of 1 N HCI in ethanol (0.0394 mol) O The resultant solution was filtered to remove foreign matter, concentrated in vacuo, and chased with ethyl acetate (400 mL). The solution was seeded repeatedly, as the solvent was removed, until crystallization was initiated. The mixture was concentrated to a volume of 100 mL, and the product was filtered and washed with ethyl acetate (25 mL). The resultant white solid was dried in a vacuum oven under a nitrogen purge at 50 °C to afford 17.6 g of the title compound.

Example 502 trans, trans-2-(2-Methylpentvl)- 4 13-benzodioxol-5-vl-1 di(n-butylaminocarbonvlmethyl)-Dvrrolidine3carboxylic acid Example 502A (±--Ethyl 3-methylhexanoate To a slurry of 60% sodium hydride (2.26g, 57 mmol) in 10mL of hexanes and 100mL of diethyl ether was added triethylphosphonoacetate (10.3mL, 52mmol). Once gas evolution ceased, 2-pentanone (6.0mL, 64mmol) was added. After 3 hours at room temperature, the reaction was quenched with water, and partitioned into ether. The organic layer was washed with water and brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in of ethanol and 10% palladium on carbon (6.0g) was added. The vessel was pressurized to 4 atmosphere of hydrogen, and was shaken at room temperature for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure to give 3.0g of the title rnmnn ind.

WO 99/06397 PCT/US98/15479 00 S-445- SExample 502B (±)-Ethyl 5-methvl-3-oxooctanoate 00 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 00 residue was dissolved in 150mL of water. The solution was washed oo with ether, then acidified with concentrated hydrochloric acid and N 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-(N.Ndi(n-butylnaminocarbonvlmethyl)-Dvrrolidine-3-carboxlic 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. 1 H 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 C28H44N2051.0 TFA* C, 58.91; H, 7.58; N, 4.58. Found: C, 58.91; H, 7.58; N, 4.45.

WO 99/06397 WO 9906397PCTIUS98/15479 00 c-i -446- Examgle c-i trans. trans-2-(2.2-Dimethylgentfl)-4-(1 .3-beflzodioxol-5-yfl)-1-(N.Ndi(n-butyflaminocarbonylmethyl-yrrolidile-3-carboxylc acid 00, Ethyl 3,3-dimethyihexanoate was prepared using the general procedure of Cahiez et aL., Tetrahedron Lett., a11, 7425 (1990). Using the procedures described in Example 502 and substituting ethyl 3,3- 00 dimethylhexanoate for ethyl 3-methylhexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFAICH3CN. I H NMR (CDC13, 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 (mn, 5H), 3.60- 3.69 (in, 1H), 3.75-3.86 (mn, IH), 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 (d, J=1.8 Hz, 1H). MS (DCI/NH3) mWe 503 Anal calcd for C29H46N205-1.05 TFA: 0, 60.01: H, 7.62; N, 4.50. Found: C, 60.21; H, 7.37; N, 4.33.

Exmple 54 trans, trans-2-(2-( 1.3-Dioxo-2-yflethyl)-4-( 1.3-benzodioxol-5-yfl)-1 D (N.N-di(n-butylaminocarboylinethYfl)pyrrolidile- 3 -caroxylic acid Examp -e 504A Ethyl 5-(1 .3-dioxolylP3a-oxopentanoate The title compound was synthesized from ethyl acetoacetate and 2-bromomethyl-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 00 for additional 10 min. To above mixture was then added 48.4 mL (0.121 inol) n-butyl lithium, a 2.50 M solution in hexane, in a dropwise m~qnnpr. The resultina orancie color solution was Stirred for 10 min WO 99/06397 WO 9906397PCT/US9815479 00 -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 of 9.8 ml (ca. 0.12 mat) concentrated 00 5 hydrochloric acid. The biphasic mixture was poured to 50 ml of water and extracted with 150 ml of ethyl ether. The aqueous layer was thoroughly with additional ethyl ether. The ethereal extracts c-I were combined, washed with 2x50 ml of saturated brine, dried over 00 0 anhydrous magnesium sulfate, filtered and evaporated under reduced Ni o pressure to give an brown oily residue. The cruae product was purified using silica gel flash chromatography eluting with 20% ether/hexane to give 5.40 g of b-keto ester as a light yellow oil.

Example 5040 trans, trans-2-(2-(1 .3-Dioxo-2-yflethyfl-4-(1 .3-benzodioxol-5-yfl-1 (N.N-di(n-butylraminocarbonylmethfl)-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate afforded the title compound. I 1 H NMR (CDC13, 300 MHz) 8 0.93 J =7.2 Hz, 3H), .0.95 J 7.2 Hz, 3H), 1.23-1.38 (in, 4H), 1.52 (sextet, J =7.9 Hz, 4H), 1.85-1.95 (in, 2H), 2.02-2.17 (in, 2H), 3.18 J 6.0 Hz, Hz, 2H), 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, 1 3.83-3.88 (mn, 3H), 3.97 (dd, J 4.8 Hz, 6.0 Hz, 1 4.05 J 9.6 Hz, 2H), 4.30-4.40 (in, 1 4.37 2H), 4.87 J 3.6 Hz, 1 5.94 2H), 6.73 J 8.1 Hz, 1 6.79 (dd, J 1.8 Hz, 8.1 Hz, 1H), 6.87 J 1.8 Hz, I1H). MS (APOI) at W/e 505. Anal calcd for C27H40N207.1.2 TFA: 0, 55.05; H, 6.47; N, 4.37. Found: C, 55.12; H, 6.44; N, 4.27.

30Exml50 trians. trans -2-(2-(2-Tet rahydro-2pyran~ethyfl-4-(1 .3-benzodioxol- N-di(n-butyflaminocarbonylmethfl)-p~yrrolidine-3- WO 99/06397 WO 9906397PCT/UJS98/1 5479 00 -448- Exa Ethyl 5-(2-tetrahydro-2Ff gyran)-3-oxopentanoate Using the procedure of Huckin and Weiler, Tetrahedron Lett. 3927, 00 (1971), the title compound was prepared from ethyl acetoacetate and 2-(bromomethyl)tetrahydro-2H-pyran as a light yellow. oil.

00 0 ~trans. trans-2-(2-(2-Tetrahydro-2H- pyran~ethyfl-4-( 1.3-benzodioxol- -(N.N-di(n-butylbaminocarbonylmetfiyfl)-oyrrolidine-3carboxylic acid Using the procedures described in Example 502 and substituting ethyl 5-(2-tetrahydro-2 H-pyran)-2-oxopentanoate for ethyl 3methylhexanoate afforded the title compound as an amorphous solid.

1H NMR (CDC13, 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, 311), 0.91 J =8.1 Hz, 3H1), 1.20-1.40 (in, 10H), 1.42-1.66 (in, 18H), 1.71 (brm, 2H), 1.85 (brm, 2H), 1.96-2.23 (brm, 3.10-3.29 (in. 8H), 3.29-3.52 (in, 3.54-3.81 (in, 6H), 4.01 J 9 Hz, 2H), 4.12-4.25 (in, 4H), 4.43 J 9 Hz, 4.50 J 2.7 Hz, 5.94 2H), 5.95 2H), 6.76 6.76 2H), 6.81 1H), 6.81 I1H). MS (APCI) at m/e 517. Anal calcd for C29H44N206*1.4 TFA: C, 56.48; H, 6.77; N, 4.14. Found: C, 56.46; H, 6.99; N, 3.83.

trans. trans-2-(2.2.4-Trimethyl-3-pentenyfl-4-( 1.3-benzodioxol-5yfl- 1 N-di(n-butyl)aininocarbonylmethyl)-pyrrolidine-3-carboxylic Exampl 0A Methyl 3.3.5-trimethyl-4-hexenoate To a slurry of isopropyltripenylphosphoniumn iodide (20.5g, 47mmol) in 200mL- of tetrahydrofuran was added n-butyllithiuin (27inL of a 1.6M solution in hexane, 43mmol), and the solution was briefly WO 99/06397 WO 9906397PCT/US98/I 5479 00 0 -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 al., Synth. Commun., 16 169 (1986) in l0mL- of tetrahydrofuran was added, and the reaction was warmed to 0 0 C for 00 30mmn. The reaction was quenched with dilute hydrochloric acid, and __partitioned with ethyl acetate. The organic layer was washed with and brine, dried with anhydrous magnesium sulfate, filtered, and cithe solvent was removed under reduced pressure. The residue was 00 purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexanes to give 2.1 g of the title-bompound.

Example 506 trans, trans-2-(2.2.4-Trimethyl-3-Dentenyfl-4-(1 yl)-l1-(N. N-di(n-butyflaminocarbonylmethyfl-pyrrolidine-3-carboy"lic acid Using the procedures described in Example 502 and substituting methyl 3,3,5-trimethyl-4-hexenoate for ethyl 3-m ethyl hexan oate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. 1 NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 1.11 3H), 1.13 3H), 1.24-1.37 (in, 4H), 1.46-1.59 (in, 4H), 1.61 J=1.2 Hz, 3H), 1.69 J=1.2 Hz, 3H), 2.04-2.11 (in, 2H), 3.10-3.20 (in, 2H), 3.30-3.39 (in, 3H), 3.67-3.82 (in, 2H), 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, I1H), 6.78 (dd, J=8.4, 1.2 Hz, 1 6.84 (d, J=1.2 Hz, 1H). MS (DCI/NH3) m/e 515 Anal calcd for C30H46N205'1.05 TFA: C, 60.77; H, 7.48; N, 4.42. Found: C, 60.83; H, 7.20; N, 4.43.

Exampe trans. trans-2-(2.2.-Dimethyl-2-(1 .3-dioxolan-2 -yl)ethyl)-4-(1 .3- N-diin-butyflaiinocarbonylmethyflpyrrolidine-3-carboxylic acid WO 99/06397 WO 9906397PCT/US98/I 5479 00 -450- Methyl 3.3-dimethyl-3-( 1 3-dioxolan-2-yfloropanoate Methyl 3,3-dimethyl-4-oxobutanoate (10Og, 7Ommol), prepared 00 according to the procedure of Hudlicky et al., Synth. Commun., 16i 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.

00 The reaction was poured into 200ml- of ether, washed with saturated ci sodium bicarbonate, water and brine, dried with "inhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to give 1 2.4g of the title compound.

Examgle 507B itrans, trans-2-(2.2.-Dimethyl-2-(1 .3-dioxolan-2-yflethyfl-4-(1 .3- N-di(n-butyflaminocarbonytlmethyl)- Dyrrolidine-3-carboxylic acid Using the procedures described in Example 502 and substituting 3methyl 3,3-d im ethyl 1,3-d ioxolIan-2 -yl) prop anoate for ethyl 3methyihexanoate afforded the title compound, which was isolated by lyophilization from dilute aqueous TFN/CH3CN. 1H NMR (CDCI3, 300 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 (in, 6H), 3.60-3.70 (in, 3H), 3.74-3.95 (in, 5H), 4.48 1H), 5.94 (in, 2H), 6.72 J=8.0 Hz, 1H), 6.83 (dd, J=8.0, 1.2 Hz, 1 6.94 J=1.2 Hz, 1 MS (DCI/NH3) m/e 533 Anal calcd for C29H44N207 -1.1 TFA*0.2 H20: C, 56.63; H, 6.93; N, 4.23. Found: C, 56.60; H, 6.96; N, 4.25.

30Exml50 trans. trans-2- 1.3-Dioxo-2-yfl ethyfl)-4- (1 .3-benzodioxol-5-yl)- 1 [Ff44-he ptyl-N.-(2-methyl-3-fluorophelyl)1 amino carbonylmethyL]- 12vrrolidine-3-carboxylic aci-d WO 99/06397 PCT/US98/15479 00 -451- Example 508A 4-HeDtanol To an ice cooled solution of 1.14g (10.0 mmol) of 4-heptanone in oo 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 S reaction was quenched by sequential dropwise addition of 0.4 mL N 0.4 mL 15% NaOH(aq), and 1.2 mL H20. After stirring another o00 0 minutes, MgSO4 was added until the salts were free flowing, then the c- 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%).

Example 508B 4-Methanesulfonyloxyheptane To an ice cooled solution of 834 mg (7.19 mmol) of 4-heptanol in mL of CH2CI2 was added 1.5 mL of triethylamine. Next, 0.7 mL (9 mmol) of methanesulfonyl chloride was added, dropwise, over 1 minute.

The mixture was stirred at 0 °C for 30 minutes, then extracted with (1 x 15 mL), 5% NH40H (2 x 15 mL), 1M HCI (2 x 15 mL), and brine (1 x 15 mL), dried over MgSO4, filtered, and concentrated to an oil. Yield 1.31g 1H 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.

WO 99/06397 PCT/US98/15479 00 S-452- Example 508D N HeDtvl-4-fluoro-3-methylaniline To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline oo s 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 N H20 and extracted with diethyl ether (2 x 30 mL). The combined ether 00 0 layers were back extracted with brine (1 x 30 mL), dried over MgSO4, c o 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 s NN.(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 o 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 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).

WO 99/06397 WO 9906397PCT1UJS98/15479 -453- ExapJgle 8 trans, trans-2-(2-(1 .3-Dioxol-2-flethfl)-4-(1 rrAL4-he ot vi -N(2-methvl-3-fluoroohe~nvfll amino rarhnnvlm~thv1pyrrolidine-3-carboxylic acid 00 Using the procedures described in Example 502, substituting ethyl 5-(1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-m ethylihexanoate and N,N-(4-heptyl)-(4-fluoro-3-methyl)phenyl-bromoacetamide for N,N- 00 dibutylbromoacetamide afforded the title compound as an amorphous S0 solid. I H NMR (CDCI3, 300 MHz) 6 0.93 (brt, 6H)- 1.23-1.47 (in, 8H1), 1.67-2.10 (in, 4H1), 2.32 3H), 3.16 J 9.0 Hz, 1H), 3.52-3.67 (brm, 2H1), 3.73 J 9.0 Hz, 1H), 3.81-4.02 (in, 6H), 4.13 (brm, 1H), 4.72 (quintet, J 6.9 Hz, 1H), 4.86 J 4.0 Hz, 1H1), 5.93 2H), 6.72 J 8. 1 Hz, 1 6.78 (dd, J 1.8 Hz, 8.1 Hz, 1 6.85 J 1.8 Hz, 1 H), 6.96 (mn, 2H), 7.08 J 9.0 Hz, I1H). MS (DCI/NH3) at in/e 599.

Anal Calcd for C33H43N207F*0.8 TFA: C, 60.24; H, 6.40; N, 4.06. Found: C, 60.21; H, 6.14; N, 3.86.

Example 0 trans, trans-2-(2-(1.3-Dioxo-2- leh 1.3-benzodioxo l-1 N-di(n-butvflam irtcarbornvlmethfl-prrlidie-3-caboxlic ~r~id Using the procedures described in Example 502, substituting ethyl (1 ,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate and 6inethoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 0.93 J 7.8 Hz, 3H), 0.95 J 7.8 Hz, 3H), 1.31 (mn, 4H), 1.53 (in, 4H), 1.90 (mn, 2H), 2.09 (in, 2H), 3.19 (dd, J 8.4 Hz, 8.4 Hz, 2H1), 3.30 J 9.6 Hz, 2H), 3.25-3.42 (in, 1H), 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, 1H1), 4.03 (dd, J 3.0 Hz, 6.3 Hz, 2H), 4.33 (in, 3H), 4.87 J 3.6 Hz, 1 5.94 2H1), 6.53 J 1.8 Hz, 1 6.63 J 1.8 Hz, 1H). 'MS (DCI/NH3) at m/e 535. Anal calcd for C28H42N208.1.05 TFA: C, 55.25; H, 6.63; N, 4.28. Found: C, 55.39; H, 6.66; N. .4.26.

WO 99/06397 WO 9906397PCTIUS98/15479 00 -454trans, trans-2-((2-Methoxyphenoxy)-methyfl-4-(1 1 -(N.N-di(n-butyl)aminocarbonylmethyfl-pyrrolidine 3-carboxylic* aci-d 00 Using the procedures described in Example 502, substituting omethoxyphenoxyacetic acid for 3-methylhexanoic acid, the above compound was prepared as an amorphous solid. 1H NMR (CDCI3, 300 0 1.55 (in, 4H), 3.05-3.25 (in, 4H), 3.28-3.55 (in, 4H), 3.58-3.68 (in, 1H), Cl 3.75-3.80 (in, 1H), 3.82 3H), 3.91 J=l4Hz, 4.05-4.15 (in, 1H), 4.23-4.33 (in, 1H),5.91 2H), 6.70 J=8Hz, 1H), 6.82-6.95 (in, 7.03 1H). MS (DCI/NH3) at m/e 541. Anal calcd for C30H40N207: C, 66.65; H, 7.46; N, 5.18. Found: C, 66.37; H, 7.61; N, 5.09.

Exml 1 (2S.3R.4S)-2-(2.2-Dimethylpentyfl-4-( 1.3-benzodioxol-5-yl)-1 h eptyl.N-(4-f Iuro-- methyl phe yl))ain oca rbonlm iethyl)pyrrolidine-3-carboxylic acid Exame 511A trans, trans- N -t ert- Buto xycarbonyl -2-L2.2 -d im ethyl pgntyfl)-4- (1 .3benzodioxol--yl-pyrrolidile-3-carboxylic acid Ethyl -trans, trans-2-(2,2-dimethylpefltyl)-4-(1 yl)-pyrrolidine-3-carboxylate (2.5g, 6.9mmol), prepared according to Example 503, was dissolved in 5Oml- of methylene chloride and di-tertb utyl di carbonate (1.5g) was added. After stirring overnight at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes to give the ethyl ester of the title compound (2.8g) as a colorless oil. The ester was dissolved in 5OmL- of ethanol followed by addition of sodium hydroxide (l0mL- of a 5M 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 WO 99/06397 PCT/US98/15479 00 O -455mixture was extracted with chloroform (3X50mL), and the organic C layers were washed wiith brine, dried over .anhydrous magnesium cN sulfate, filtered, and the solvent was removed under reduced pressure to give the title compound (2.4g) as a white foam.

oo SExample 511B Methyl trans, trans-2-(2.2-dimethylpentyl)-4-( 1.3-benzodioxol-5-vyl- 1 -(N-4-heotvl-N-(4-fluoro-3-methvylhenyl~aminocarbonvlmethyl)oO 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 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 S dropwise addition of the lithium oxazolide suspension via cannula.

After 30min, the reaction was partitioned between ether and saturated bicarbonate. The organic phase was washed with water then brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate/hexanes to give the undesired diastereomer (1.17g, then elution with ethyl acetate/hexanes gave the desired diastereomer (1.04g, 38%).

The desired diastereomer of the N-acyloxazolidinone (0.84g, 1.42mmol) was dissolved in 2.5mL of dichloromethane, and 2.5mL of trifluoroacetic acid was added. After 30min, the volatiles were removed under a stream of nitrogen, and the residue was twice dissolved in 5mL of toluene and evaporated under reduced pressure.

The TFA salt was stirred with 4mL of acetonitrile followed by addition of diisopropylethyl amine (1.OmL, 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 WO 99/06397 PCT/US98/15479 00 c- -456- Swarmed to 500C for 3.5 hours. The reaction was cooled, the solvent C removed under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with 20-30% ethyl 0 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, S 0.53mmol) was added at 0°C, followed by 30% hydrogen peroxide 00 (0.050mL, 0.55mmol). After 1 hour, the reaction was warmed to room O temperature. After an additional hour, the reaction was partitioned 3 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 lmL 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 o 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-Dimethylpentyl4- 4 -(1.3-benzodioxol-5yv)-l-(N-4-heDtyl-N-(4-fluoro-3methyl henyl)aminocarbonvlmethyl)-pvrrolidine-3-carboxylate The product from Example 510B (65mg, 0.10mmol) was dissolved in 1.0mL of methanol and sodium hydroxide (0.1mL of a SM 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 WO 99/06397 WO 9906397PCT/US98/15479 00 -457- S from dilute aqueous TFAICH3CN. 1 H NMR (CDCI3, 300 MHz) d 0.78-0.95 (in, 15H), 1.04-1.46 (in, 12H), 1.76-2.95 (in, 2H), 2.31 3H), 3.23-3.33 (in, 1H), 3.47-3.58 (in, 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 (mn, 2H), 6.82-6.93 00 (in, 2H), 6.96-7.14 (in, 2H). MIS (DCI/NH3) W/e 597 Anal calcd for C35H49N2F05 -0.05H20 *,0.8TFA: C, 63.81; H, 7.30; N, 4.07. Found: 21 C, 63.84; H, 7.18; N, 3.94. [ab =+460 (c 2.7gfL, CHCI3) 00 Example 12 trans, trans -2 Oxopyrroli6d n1 -yfl ethyfl-4 .3-ben yfl)-1-(N. N-di(n-butyl)aminocarbonylmethyfl-pyrrolidine-3-carboxytlic =Wi Fxampl 52A 2-Oxopyrrolidin-1-yloropionic acid To a stirred solution of 5.0 mL (40.5 mmol) 2-oxopyrrolidin-1ylpropionitrile in 15 mL of dioxane was added 8.1 mL of hydrochloric acid, a 6.0* M aqueous solution. The resulting mixture was then ref luxed I at 110 00 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.

Example 512B Ethyl* 5-(2-oxopyrrol idin- 1 -l-3-oxopentanoate The title compound was prepared from the above acid by adapting the method of Brain and Vilkas, Bul. Chemn. Soc. Fr., 945 (1964).

WO 99/06397 WO 9906397PCTIUS98/I 5479 00 -458- Examlle 512C trans, trans -2 (2-Oxopyrrol idi n- 1 -yl~ethyfl-4-( 1.3-be n zodi yl)-l -(N.N-di(n-butyflaminocarbonylmethyfl)-Dyrrolidlne-3-carboxyllc aw 00~ Using the procedures described in Example 502, substituting ethyl 5-(2-oxopyrrolidin-1-yl)-3-oxopentanoate for ethyl' 3ci methyihexanoate afforded the title compound as an amorphous solid.

00 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 (m 2.05 6.9 Hz, 2H), 2.12- 2.25 (in, I1H), 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47-2.61 (mn, 1 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J 9 Hz, 1 3.32 J 7.8 Hz, 2H), 3.38-3.48 (in, 3H), 3.52 J 9 Hz, 1H), 3.66 J 6.9 Hz, 1H), 3.96 (mn, 2H), 4.14 (in, I1H), 4.38 (brs, 2H), 5.93 2H), 6.74 J 8.1 Hz, 1H), 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1H), 6.87 J 1.8 Hz, I1H). MIS (DCI/NH3) at Wne 516. Anal calcd for C28H41N306-1.4 TFA: C, 54.78; H, 6.33; N, 6.22. Found: 0, 54.69; H, 6.33; N, 6.14.

Example 513 3 trans, trans-2-(2-(1 .3-Dioxol-2-yflethyfl-4-(7-methoxy-I 3 benzodioxol-5-yl'-l1-( N-4-heptyl-N-(4-fluoro-3m ethylphe nyl)am inca rbonyl meth yfl-pyrrolid ie-3-carboxyl ic acid Using the procedures described in Example 502, substituting ethyl 5-(1,3-dioxolyl)-2-oxopentanoate for ethyl 3-methylhexanoate, N-4heptyl-N-(4-fluoro-3-methylphenyl) bromoacetamide for N,N-dibutyl bromoacetamide and 6-methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDC13, 300 MHz) 8 0.93 (br t, 6H), 1.23-1.47 (mn, 8H), 1.67-2.10 (mn, 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, 1H), 4.86 J 3.6 Hz, 1H), 5.93 2H), 6.49 1H), 6.61 1H), 6.96 (in, 2H), 7.08 J 9 Hz, 1H). MS (DCI/NH3) at mle 629. Anal calcd for C34H45N208F.1.Q TFA: C, 58.21; H, 6.24; N, 3.77.

Found: C, 58.11: H, 6.11; N, 3.58.

WO 99/06397 WO 9906397PCT/US98/15479 00 .459- Example514 trans, trans-2-(2.2-Dimethyllentyfl-4-(7-methoxy-1 yl)-1 -(N.N-di(n-butyl)aminocarbonylmethyfl)-pyrrolldine.3-carboxylic 00 i Using the procedures described in Example 502, substituting ethyl 5-methyl-3-oxooctanoate for ethyl 3-methylhexanoate and 6- 00 methoxypiperonal for piperonal afforded the title compound as an amorphous solid. 1 H NMR (CDCI3, 300 MHz) 8 0.81 3H), 0.84 3H), 0.86 J 6.9 Hz, 3H), 0.93 J 6.9 Hz, 3H), 06 J 6.9 Hz, 3H), 1.09-1.38 (in, 8H), 1.45-1.59 (in, 4H), 1.84-2.00 (in, 2H), 3.15 (dd, J 6.9 Hz, 10.0 Hz, 2H), 3.30-3.42 (in, 3.72 J 10.5 Hz, 3.86 (t, J 10.5 Hz, 1H), 3.88 3H), 4.02 J 10.0 Hz, 1H), 4.12 J 16.8 Hz, 1 4.29 J 16.8 Hz, 1 4.41 (bin, 1 5.94 1 6.52 J 1.8 Hz, 1H), 6.67 J 1.8 Hz, 1H). MS (DCI/NH3) at m/e 533.

Anal calcd for C30H48N206-0.9 TEA: C, 60.12; H, 7.76; N, 4.41. Found: C, 60.18; H, 7.62; N, 4.33.

trans. trans-2-(2.2-diinethylr~entyl)-4-(2.3-dihydro-benzofuran-5-yfl- I -(N.N-di(n-butyl)aininocarbonylmethyfl-pyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting ethyl 3,3-dimethylhexanoate for ethyl 3-inethylhexanoate and 2,3-dihydrobenzofuran-5-carbaldehyde for piperonal afforded the title compound as an amorphous solid by lyophylization with CH3CNITFA/H20. 1H NMR (300 MHz, CDCI3) 8 0.83 3H), 0.85 3H), 0.86 J=7.2 Hz, 3H), 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 1.09-1.39 (in, 8H), 1.44-1.59 (in, 4H). 1.88 (dd, J=15.0, 7.2 Hz, 1H), 2.00 J=1 5.0 Hz, 1H), 3.09 (mn, 2H), 3.18 J=9.0 Hz, 2H), 3.27-3.38 (in, 3H), 3.65-3.95 (mn, 2H), 4.05 (q, J=10.0 Hz, 111), 4.18 J=16.8 Hz, 4.30-4.45 (in, 4.55 Hz, 2H), 6.70 J=8.4 Hz, 1H1), 7.04 (dd, J=8.4, 2.1 Hz, 7.23 (brs, 1H). MS (DCl/NH3) at m/e 501 Anal calc'd for C30H48N20 4 .1.05 TFA: C, 62.14; H, 7.97; N, 4.51. Found: C, -62.19; H, 8.00; N, 4.43.

WO 99/06397 WO 9906397PCT/UJS98/I 5479 -460- Example 516 trans, trans-2-(2.2 @-Dim ethyl-2 .3-d io xol an -2-yi) ethyfl)-4-( 1methoxy-1 .3-benzodioxol-5-yfl-1-(N.N-dl(flbutyflarninocarbonylmethyl-yrrolidie-3-carboxyic acid 00 Using the procedures described in Example 502, substituting 3.3- dim ethyl ,3-d ioxol an -2-yI) prop afoate for ethyl 3- 00 methythexanoate and 6-methoxypiperoflal for piperonal afforded the 0 title compound as an amorphous solid by lyophylization with Ni 0 CH3CNITFAIH2O. 1 H NMR (CDC13, 300 MHz) 8 0.93 J=7.2 Hz, 3H), 0.94 J=7.2 Hz, 3H), 0.95 3H), 0.96 1.31 (sextet, J=7.2 Hz, 4H), 1.45 (in, 4H), 1.93 (dd, J=15.9. 6.0 Hz, IH), 2.13 J=15.9 Hz, 1H), 3.20 (dd, J=7.7. 7.7 Hz, 1H), 3.26-3.40 (in, 3H), 3.60 (in, 1H), 3.75-3.86 (in, 3H), 3.88 3H), 3.93-4.01 (in, 3H), 4.00-4.11 (in, 1H), 4.23 J=15.9 Hz, 1H), 4.37-4.48 (in, 2H), 4.49 1H), 5.94 2H), 6.51 J=2.1 Hz, 1H), 6.64 J=2.1 Hz, I1H). MS (DCI/NH3) at mWe 563 Anal calIcd for C30H46N208-0.9 TFA: C, 57.41; H, 7.11; N, 4.21; found: C, 57.35; H, 6.86; N, 4.05.

!0Ea pt-1 trans. trans-2-(2-(2-Methoxyphellethyl) 4 1 .N-di(n-butyflaminocarboflyrfethyl)-Dyrrolidifle- 3 -carboxylic acid Using the procedures described in Example 502, substituting omethoxyphenyipropionic acid for 3-methylhexanoic acid,- the above compound was prepared as an amorphous solid. 1 HNMR (CDC13, 300 MHz) 8 0.85 J=7Hz, 3H), 0.91 J=7Hz, 3H), 1.10-1.27 (in, 4H), 1.42- 1.60 (in, 4H), 1.72-1.89 (in, 1H), 1.91-2.02 (mn, 1H), 2.55-2.77 (in, 2H), 2.94 J=6Hz, 1H), 3.05-330 (in, 6H), 3.59-3.82 (in, 311), 3.73 (d, J=l4Hz, 1H), 3.77 3H), 5.91 2H), 6.70 J=8Hz, 1H), 6.78-6.88 (in, 3H),6.92 J=2Hz, I 7.08-7.19 (in, 2H). MS (DCl/NH3) at m/e 539. Anal calcd for C31H42N206: C, 69.12; H, 7.86; N, 5.20. Found: C, 68.89; H, 7.70; N. 4.99.

WO 99/06397 WO 9906397PCTIUS9815479 00 -41- Example 51 trans. trans-2-(2.2-D im ethyl -3-(E)pentenyfl-4-(1 -m elhoxv- 1.3 benzodioxol-5-yll-1 N-di(n-butyflaminocarbonylmethyflpyrrolidlne-3-carboxylip acid 00 4-Methyl-2-12enten-2-ol 00 To a stirred solution of 3-methyl-2-butenal (8.7g, lO3mmol) in ci lOOmL of tetrahydrofuran under N2 at 0 OC was added methylmagnesium bromide (3BmL 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-di methyl -4-pe nte noate A mixture of 4-m ethyl- 3-p enten-2-olI (7.4g, 74mmol), triethyl orthoacetate (13.6mL, 74mmol) and propionic acid (O.2BmL, 3.7mmol) was heated at 150 00C for 7 hours. The product was then distilled under normal pressure (200-220 00) to give 5.Og of crude ester as a colorless oil.

trans, trans-2-(2.2-Dimethyl-3-(E-D2entenyfl-4-(1 -methoxy-1 .3benzodioxol-5-yl)-l1-(N. N-di(n-butyflaminocarbonylMethyfl- Dyrrolidine-3-carboxylic acid Using the procedures described in Example 502, substituting trans-ethyl 3,3-dimethyl-4-pentenoate for ethyl 3-methylhexanoate and 6-methoxypiperonal for piperonal afforded the title compound. as an WO 99/06397 WO 9906397PCTIUS98II 5479 00 -462amorphous- solid by lyophilization from dilute. aqueous TFAICH3CN. 1

H

NMR (CDCI3, 300 MHz) 8 0.92 J=7.2 Hz, 3H), 0.95 J=7.2 Hz, 3H), 0.97 3H), 0.99 3H), 1.31 (sextet, J=7.2 Hz, 4H), 1.52 (quintet, 00 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 (mn, 2H), 3.87 3H), 3.99 J=9 Hz, 2H), 4.11-4.30 (in, 3H), 5.29 (d, 0N J=15.6 Hz, 1H), 5.38 (dd, J=15.6, 6 Hz, 1H), 5.94 2H), 6.50 J=1.8 00 Hz, 1H), 6*.63 J=1.8 Hz, 1H). MS (DCI/NH3) at Wne 531 0 Analysis calc'd for C30H46N206-0.95 TFA: C, 59.95; H, 7.41; N, 4.38; found: C, 60.00; H, 7.33; N, 4.35.

Examole 519 trans, trans-2-(3-(2-pyridyflethyfl-4-(1 .3-benzodioxol-5-yfl-1-(N.Ndi(n-buty-flaminocarbonylmethyl-yrrolidinle-3-carboxylic acid Example 519A 3-(2-Pyridyfl-propionic Acid In a 50 mL round-bottomed flask equipped with a stirring bar was 0 placed 3-(2-pyridyl)-propanol (1 g, 7.6 mmol), water (13 mL) and concentrated sulfuric acid (0.5 g, 5.1 mmol). To this stirred solution was added over a period of 30 min potassium permanganate (1.8 g, 11.3 minol) 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 0 C for 1 hour and filtered. The filtrate was evaporated to dryness to yield quantitatively the desired acid (1.14 g) suitable for next step without further purification. To prepare a pure acid, the residue thus obtained was boiled in ethanol (10 mL) in the presence of charcoal (0.1 g) for min, filtered and cooled to give crystalline 3- (2-pyridyl)-propionic acid (0.88 g, 78%).

WO 99/06397 WO 9906397PCTIUS98/I 5479 00 -463- Example 519B trans. trans-2-(3-(2-pyri dyfl)ethyfl)-4-(1 .3-benzodi oxoI- 5-yfl Ndi(n-butyflaminocarbonylmethyfl)-yrrolidine-3-carboxylic acid 00 Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFAICH3CN as an 0 ~amorphous solid. 1HNMR (CDCI3, 300 MHz) 8 8.65 J=6.0 Hz, 1 8.06 00 J=6.91 Hz, 1 7.70 J=9.0 Hz, 1 7.51 J=6.91 Hz, 1 6.82- 6.66 (in, 3H), 5.91 2H), 4.45 2H), 4.29-4.18 1IH), 4.04 (dd, J=20.1, 10.5 Hz, 1 3.84 J=12.6 Hz, 1 3.62 (dd, J=13.8, 9.6 Hz, 1 3.46-3.13 (in, 7H), 2.51 (broad s, 2H), 1.60-1.43 (mn, 4H), 1.37-1.22 (in, 4H), 0.91 J=8.4 Hz, 6H). MS (DCI/NH3) mWe 510 Anal calcd for C29H39N305*1.75 TFA: C, 55.04; H, 5.79; N, 5.92. Found: C, 55.08; H, 5.64; N, 5.81.

(2S. 3R. 4S)-2-(2-(2-oxopyrrolidin-1 -yflethyfl-4-(1 yf)l-(N. N-di(n-butylaminocarbonylmethyfl)-Dyrrolidine-3-carboxylic Exam~e (2iS. 3R. 4,S)-Ethyl.2-(2- (2-oxopyrroli din- 1-yliethyl) (1 .3ben zod ioxo 1-5-yl~pyrro li din e-3-ca rboxyl ate-(SI-Mandelate The racemic amino ester from Example 512 (3.45g, 8.9Bmmol) in lOmL of ethyl acetate was treated with (S)-(-i)-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.

WO 99/06397 WO 9906397PCT/US98/15479 00 -464- (12S. 3R. 4S-Eth yl-2-(2-(2-oxopyrrolidin- 1-yflethyl)-4-( 1.3benzodioxol-5-yfl-1 N-di(n-butyflami nocarbonylm ethyl)pyrrofidine-3-carboxylate 00' To a stirred solution of pure mandelate (150 mg, 0.28 mmol) in CH3CN was added NN-dibutylbromoacetamide(84 mg, 0.34 mmol) and N dilsopropylethylamine (9BuL, 0.56mmol). The resulting mixture was 00 stirred at room temperature over night. Solvent was then removed cI under reduced pressure and the crude product wa-s purified by silica gel flash chromatography to give 140 mg (90% yield) of the title compound.

(2S. 3R. 4S)-2-(2-(2-oxopyrrolidin-1 -yl~ethyfl-4-( 1.3-benzodioxol-5yfl- N-diln -butyfl)am inocarbonylm ethyl-pyrrolidi ne-3-carbOxylic Using the procedures described in Example 502, the title compound was prepared as an amorphous solid by lyophylization with CH3CNlTFAIH2O. I 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 (m 2.05 J 6.9 Hz, 2H), 2.12-2.25 (in, 1 2.38 (td, J 4.2 Hz, 8.4 Hz, 2H), 2.47- 2.61 (mn, 1 3.17 (dd, J 6.0 Hz, 8.7 Hz, 2H), 3.24 J 9 Hz, 1 3.32 J 7.8 Hz, 2H), 3.38-3.48 (mn, 3H), 3 .52 J 9 Hz, I1H), 3.66 J 6.9 Hz, 1 3.96 (in, 2H), 4.14 (in, I1H), 4.38 (brs, 2H), 5.93 6.74 J 8.1 Hz, I 6.89 (dd, J 1.8 Hz, 8.1 Hz, 1 6.87 J 1.8 Hz, 1H). MS (DCI/NH3) at mWe 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.

WO 99/06397 WO 9906397PCTIUS98/15479 00 -465- U2S, 3R. 4S'-2-(2-(2-ox~gyrroli din- 1-yflethyfl-4-(1 .3benzodioxol-5-yf)l-(N-4-heltyl-N-(4-fluoro-3methylphenyfl)aminocarbonylmethyl)-Dyrrolidine-3-carboxylic acid 00 Using the procedures described in Example 520, substituting N,N- 5(4-heptyl)-(4-f luoro-3-methyl)phenyl-bromoacetamide for N,Ncidibutyibromoacetamide afforded the title compound as an amorphous 00 solid by lyophylization with CH3CN/TFA/H20. 1H NMR (CDCI3, 300 MHz) 8 0.85-0.98 (in, 6H), 1.22-1.55 (in, 8H), 2.04 (quiffiet, J=7.9 Hz, 4H), 2.32 3H), 2.36 J=7.9 Hz, 2H), 2.61 (in, 1H), 3.14 (mn, 1H), 3.25-3.61 (in, 5H), 3.66-3.77 (in, 1H), 3.79-3.90 (in, 2H), 3.92-4.03 (in, 1H), 4.69 (quintet, J=6.8 Hz, 1H), 5.95 2H), 6.71 2H), 6.78 1H), 6.93-7.13 (mn, 3H): MS (DCI/NH3) at Wne 610 Anal calc'd for C34H44N306F 1 1.45 TFA: C, 57.18; H, 5.91; N, 5.42. Found: C, 57.20; H, 5.62; N, 5.52.

trans. trans-2-(2-(1 -Dyrazolyflethyl)-4-(1 .3-benzodioxol-5-yfl-1 (N.N-di(n-butyflaminocarbonylmethyl-yrrolidine-3-carboxylic acid Exampi, 22A 3-(1 -Pyrazolyfl)-rogionic Acid In a 10 mL round-bottomed flask equipped with a condenser and a stirring bar was placed pyrazole (0.50 g, 7.3 iniol), acrylic acid (0.50 mL, 7.3 iniol) and triethylamine (3 mL). The reaction mixture was ref luxed 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.

WO 99/06397 WO 9906397PCT/US98/15479 00 -466trans. trans-2-(2-( 1-ogyrazolyflethyl)-4 1.3-benzodioxol-5-yfl)-1- N-di(n-butylaminocarbonylmethyfl-yrrolidile-3-carboxylic acid 00 Using the procedure described in Example 502, the title compound was isolated by lyophilization from dilute aqueous TFAICH3CN as an amorphous solid I NMR (CDCI3, 300 MHz) 8 7.56 J=3.0 Hz, 1 7.50 (d z .36.6( ,3 .8(,J3 z 00 (,J3H,1) .366 i,3) .8(,J3H,1) 4.55-3.98 (in, 6H), 3.83-3.72 J=10.5 Hz, 1H), 3.61-3.40 J=10.5 Hz, CI 1 3.36-3.12 (in, 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). MS (DCI/NH3) at mWe 499 Anal calcd for 027H38N405-0.75 TFA: C, 58.60; H, 6.69; N, 9.59. Found: C, 58.53; H, 6.45; N, 9.67.

E xam2le52 trans. trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl-l -r(Nbutyl-N-(3-hydroxygrOlylamifloicarbonylmlethyl1Dpyrrolidine- 3 crboyic acid 0 ExamlDle 523A N-Butyl-N-(3-hyd roxyoropyl)-aminea To a solution of 15.9g (100 minol) of methyl 3-N-(nbutyl)aminopropionate in 150 mL of diethyl ether at 0 'C was added mL (0.35 minol) of 1 .OM LiAIH4 in diethyl ether, keeping ref lux at a minimum. The mixture was stirred at 0 .0 for 2.25 hours, the quenched by sequential dropwise addition of 1.9 mL H20, 1.9 mL NaOH(aq), and 5.7 mL H20. After stirring for 30 min, the salts were filtered and washed with diethyl ether, then the filtrate was concentrated to 11.3 g of a light yellow oil.

Examle 23B N -Butyl- N- (3-hydroxyp ropyl) -chi oroacetami de 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 WO 99/06397 WO 9906397PCT/US98/I 5479 00 -467- 1 .71g (10.0 mmol) of chloroacetic 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 00 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.

00 0 ~Examp~l 23C ci trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-ben-iodioxol-5-yl)-1 bUtyl-N-(3-hydroxyprogyflamino~carbonylmethyll-pyrrolidine-3carboxylic acid Using the procedures described in Example 1D, substituting Nbutyl-N-(3-hydroxypropyl)-chloroacetamide for N-propyl bromoacetamide and adding DMS0 as cosolvent, afforded the title compound, which was isolated by lyophilization from dilute aqueous TFA/CH3CN. I1 NMR (CD3OD, 300 MHz) 8 0.78-0.95 (in, 3H), 1.00-1.80 (in, 4H), 2.80-3.65 (in, 15H), 3.80 J=1.5 Hz, 2H), 5.93 2H), 6.72- 7.05 (mn, 5H), 7.33-7.40 (in, 2H). MS (DCI/NH3) at m/e 513 Anal calc'd for C28H36N207-1.6 H20: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.04; H, 7.2 1; N, 4.88.

Examl 24 trans- trans-2-(4- Met hoxyph enyt)-4- (1 .3-benzodioxol-5-yl) -1 -r(Npropyl-N-12roooxyamino~carbonylmethyl1-pyrrolidine-3-carboxylic acid Examl 24A N-Boc-O-allylhydroxylainine 0-Allylhydroxylamine hydrochloride hydrate (5.0g) was dissolved in THF (15 inL). The solution was cooled to 0 0 C in an ice bath.

Diisopropylethylamine (8mL) and di-t-b utyl di carbonate (1 0.0g) were added. The mixture was stirred at 0 0 C for 1 hour at which point the bath was removed and the reaction allowed to warm to room WO 99/06397 PCT/US98/15479 00 -468temperature and stirred overnight. The THF was removed in vacuo and Sthe 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 oo with sodium sulfate and evaporated to give a light yellow oil which was used without any further purification.

SExample 524B 0 N-Boc-N-oroovl-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 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 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-propol-N-proDoxvamine 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).

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -469- N-Progyl-N-12ropoxyamine hydrochloride N-Boc-N-propyl-N-propoxyamine (5.8g) was dissolved in 4N 00 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 N- washed with diethyl ether.

00 Example- 524E N-1D ropyl-N-proDoxy-bromoacetamide N-Propyl-N-propoxyamine hydrochloride (0.30 g) was dissolved in acetonitrile and cooled to -200C. Pyridine (0.2 ml-) was added.

Bromoacetyl bromide (0.15g) was added dropwise over 5 min. The solution was stirred at -2000 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 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.

Examole--524F trans, trans-2-(4-Methoxyphenyfl-4-(1I.3-benzodioxol-5-yl)- 1-r(Lbutyl-N-(3-hydroxyoropyli amino)carbonylmethyll-gyrrolidine-3carboxylic acid Prepared according to the procedure of Example 523C, employing N-propyl-N-propoxy-bromoacetamide and ethyl 2-(4-methoxyphenyl)- 1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate. The crude product was purified by preparative HPLC (Vydac mCl8) eluting 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 (CDC13, 300 MAHz) 8 0.87 (in, 6H, J=8Hz), 1.49 (in, 2H, J=BHz), 1..61 (in, 2H, J=8Hz), 3.55 (in, 6H), 3.80 (in, 2H), 3.81 3H)1, 4.00 (in, 2H), 4.13 2H, WO 99/06397 PCT/US98/15479 00

O

-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.

005 Example 525 0 trans, trans-2-(4-Methoxyvhenvll-4-(1.3-benzodioxol-5-vyl-1-r(N- 00 butyl-N-oropoxvamino)carbonylmethyll-yrrolidine-3-carboxvlic acid N o 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 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.

Example 525B !o N-Butvl-N-(2-azidoethyl-chloroacetamide To 500 mg of N-butyl,N-2-hydroxyethylamine was added 2 mL of thinoyl chloride, dropwise. After the initial reaction had ceased, the reaction was stirred for 10 min, then concentrated to an oil. Diethyl ether was added and evaporated to aid in removal of the thionyl chloride. The residue was taken up in 10 mL of DMF, and 1.0g (16 mmol) of sodium azide was added. The reaction was stirred at 75 'C for 2 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 WO 99/06397 WO 9906397PCTIUS98/15479 00 -471chromatography, eluting with 30% ethyl acetate: hexanes, to give 161 mg of an oil.

Example 5250 00 trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yfl)-1-r(Nbutyl.N-(2-aminoethylamino~carbolylmethyl]-pyrrolidifle-3carboxylic acid 00 According to the procedure of Example 523C, N-butyl-N-(2- I azid oethyl)- ch o roacetami de was coupled with 61hyl 2-(4- Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidifle-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 i 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 IN 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 lmL of 1M HCl(aq.), 0.5 mL of dioxane, 0 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. I NMR (CD3QD, 300 MHz) 8 0.92 J=7.0 Hz, 0.96 rotamer), 1.23 (in, 2H), 1.41 (mn, 2H), 3.06 (mn, 4H), 3.39 (in, 2H), 3.69 (in, 2H), 3.84 (s, 3H), 3.94 (in, 3H), 4.18 (in, 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 (in, 3H), 7.56 (in, 2H). MS (DCI/NH3) at m/e 498 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.

WO 99/06397 PCT/US98/15479 00 O -472- Example 526 trans. trans-2-(4-Methoxvyhenvy-4-(1.3-benzodioxol-5-vl-1 -r(Nbutyl-N-(3-aminoDropyl)amino)carbonylmethyll-Dprrolidine-3carboxylic acid 00 To and ice-cold solution of the compound of Example 523C (100 0 mg, 0.19 mmol) in 1 mL of dichloromethane was added 17mL of 0o methanesulfonyl chloride, and 39 mL of triethylamine. The mixture S was stirred for 20 min, then diluted with 1.5 mL of dichloromethane N( and extracted once with 5mL of water to which had been added 1 drop of 85% H3P04, then 5% ammonium hydroxide (1 x 2.5 mL), and brine (1 x mL), dried over MgSO4, filtered, and concentrated to an oil. To a solution of 81 mg (0.13 mmol) of the mesylate in 1mL of DMF was added mg (10 mmol) of sodium azide. The mixture was stirred for 1 hour i 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 3 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) (M+H) at m/e 512. Anal calcd for C28H37N306-3.0 TFA: C, 47.84. H, 4.72. N, 4.92. Found: C, 47.86; H, 4.75; N, 4.97.

WO 99/06397 WO 9906397PCT/US98/1 5479 00 -473- Examge 52 trans, trans-2-(4-Methoxyphenyl)-4-( 1.3-benzodioxol-5-yl)-l1-r(Nbutyl- N-(3-di methyl am inop ro 1yi) amino) carbo nyl methyll-pyrrol id ine-3= 00 5 carboxylic acid Example 527A 00 N-butyl-N-(3-bromopropyl)b-romoacetamide To 1 .50g (11.4 mmol) of N-butyl-N-(3-hydroxy)propylamine was added 3 mL of 48% HBr(aq.), and 1.5 mL of conc. 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 *C 0 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.

Ethyl trans. trans-2- Met hoxyphe nyl)-4-(1 ben zod ioxo 1-5-yfl)-1 r(N-butyl.N-(3-bromopropyflaminocarbonylmethyl-Pyrrolidine- 3 carboxylate According to the procedure of Example 523C, N-butyl-N-(3bromnopropyl-bromoacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-(1 ,3-benzodiox ol-5-yl)-pyrrolidine-3-carboxylate.

The crude product was chromatographed on silica, using 40% EtOAc in hexanes to elute.

WO 99/06397 WO 9906397PCT/US98/15479 00 -474ci trans. trans-2-(4-Methoxyphefl)l-4-( 1.3-benzodioxol-5-yi)-1 -r(Ncarboxylic aci-d 00 To 400 mg (0.663 mmol) of the compound of Example 527B in 4 0 mL of absolute EIOH was added 1.2 mL of 2.0 M Me2NH in THF. The 00 reaction was heated at 50 .0 for 3h, then stirred at room temperature for 18 hours. The mixture was concentrated, then reconcentrated from c-i 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 I N H3P04. and the product was purified by preparative HPLC. 1H NMR (CD3OD, 300 MHz) 8 0.92 (t.

Hz, 3H), 1.22 (in, 2H), 1.39 (in, 2H), 1.90 (in, 2H), 2.87 6H), 3.07 (in, 4H), 3.24 (in, 1 3.43 (mn, I1H), 3.62 (in, I1H), 3.84 3H), 3.88 (in, 3H), 4.07 (in, I 4.17 (in, 1 4.97 (in, 1 5.97 2H), 6.83 J=8-1 Hz, 1 6.93 (dd, J= 1.7, 8.1 Hz, 1 7.05 (in, 3H), 7.53 (mn, 2H). MS (DCI/NH3) at Wne 540 Anal calcd for C30H41 N306-2.95 TFA: C, 49.22. 5.06. N, 4.80. Found: C, 49.16; H, 5.11; N, 4.62.

Exampl 52 trans. trans2-(4-MethoxyPhenyl- 4 3-benzodioxol-5-yl)-1 -r(Nb-u-tyl -N tri methyl ammo nip prop yl ~am ino ~ca rbon ylnethyl1 pyrrolidine-3-carboxyli-c acid Prepared according to the procedures of Example 5270, substituting aqueous Me3N for Me2 NH- 1 H NMR (CD3OD, 300 MHz) 8 0.91 (in, 3H), 1.24 (in, 2H), 1.40 (in, 2H), 1.99 (in, 2H), 3.13 9H), 3.18 (s, rotamer), 3.20 (mn, 3H), 3.39 (mn, 4H), 3.72 (mn, 1 3.84 3H), 4.03 (in, 3H), 4.35 (mn, 1 5.19 (mn, 1 5.97 2H), 6.84 J=8.1 Hz, 1 6.96 (dd, J=1.7, 7.9 Hz, 1H), 7.10 (in, 3H), 7.62 (in, 2H). MS (DCI/NH3) at W/e WO 99/06397 PCT/US98/15479 00 S-475- S 554 (M+H) Anal calcd for C31H44N306*0.1 H20*1.65 TFA: C, 47.25.

M H, 4.96. N, 4.32. Found: C, 47.25; H, 4.74; N, 4.75.

Example 529 S trans. trans-2-(4-Methoxyhenylv-4-(1.3-benzodioxol-5-vl-1 Sbutyl-N-(4-aminobutyllamino)carbonvlmethyl]-pyrrolidine-3- O carboxylic acid oo 00 SExample 529A N-butyl-N-(4-hydroxybutyl)-amine A solution of 8.1 g (110 mmol) of n-butylamine and 8.6 g of butyrolactone in 50 ml toluene was allowed to reflux under nitrogen atmosphere for 50 hours. Volatile solvents were removed in vacuo. To a solution of 3.18 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 o 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 529B N-butyl-N-(4-hydroxybutyl)-chloroacetamide 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.

WO 99/06397 PCT/US98/15479 00 -476- Example 529C Ethyl trans, -trans-2-(4-Methoxvohenvil-4-(1 .3-benzodioxot-5-vi)l1 I(N-butvi-N-(4-hydroxvbutvlaminocarbonvmtvlvroiiecarboxylate oo According to the procedure of Example 5230, N-butyl-N-(4hydroxybutyl-chloroacetamide was coupled with ethyl 2-(4- 00 Methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product was chromatographed on silica gel.

Example 5290 Ethyl trans. trans-2-(4-Methoxvhenvl- 4 .3-benzpdioxol-5-vYl-1 ((N-butvi-N-(4-bromobutvlaminocarbonvimtyloroiie3 carboxylate To the solution of 0.180 gm (0.33 mmol) of the compound of Example 529C in 2 mi DMF 0.086 gm (1 mmol) of lithium bromide and 0.120 mi (0.66 mmol) of PBr3 was added. The reaction mixture was allowed to stir at 0'0 for 2 hours and was slowly warmed to room o 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.

Eampl 529E tranS. trans-2-(4-Methoxv1.3-benzodioxo-b i-(NbItyl-N-(4-aminobutyl)amino)carbonlm hyI1P rr iine 3 carboxylic acid To a solution of 0.135 gm (0.21 mmol) of the compound of Example 529D in 2 mi 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 mi 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.

WO 99/06397 WO 9906397PCT/US98/1 5479 00 8 477- 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 roomn temperature. The solution 00 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. IH NMR (CD3OD, 300 00 MHz) 8 0.90 J=7 Hz, 3H), 1.10-1.65 (in, 6H), 2.85-2.95 (in, 2H), 3.00- 4.10 (in, 14H), 5.50 J=3 Hz, 2H), 5.97 2H), 6.82 J=8 Hz, I1H), 6.91 (dd, J=7 Hz, 1H), 7.00-7.06 (in, 3H), 7.45-7.55 (mn, 2H). MS (DCI/NH3) at W/e 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.

trans. trans-2-(4-Methoxyphenyfl-4-(l .3-benzodioxol-5-yfl)-1-r(Nbutyl-N-(4-dimethyl aminobutyl amino~carbonylmethyll-pyrrolidine-3- The title compound was prepared from the compound of Example 529D, employing the procedures of Example 527C. 1H NMR (CD3OD, 300 MHz) 0.90 (dt, J=7Hz, 3H), 1.1-1.75 (in, 8H), 2.75 J=7 Hz, 6H), 4.25 (in, 16H), 5.97 2H), 6.83 J=8 Hz, 1 6.93 (dd, J=8 Hz, 1 H), 7.02-7. 08 (in, 3H), 7.49-7.56 (in, 2H). +MS (DCI/NH3) at mWe 554 Anal calc'd for C31 H43N306-2.1 TFA: C, 53.31; H, 5.73; N, 5.30. Found: C, 53.50; H, 5.38; N, 5.34.

Exampi 53 trans, trpns-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)-1 -r(Nbutyl-N-(3-pyridyl)agmino)carbonylmlethyll12yrroldine-3carbox~ilic Example531A N -but yl -N -(3-2y rid amn To a solution of 941 mg (10 minol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH30H was added 10 mL of glacial acetic WO 99/06397 WO 9906397PCT/US98/15479 00 -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 cyanoborohydride was added. The ice bath was removed, and the reaction was stirred for 4.5 hours at room temperature. The mixture 00 I 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 00 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.

trans. trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-yl)-1 -rNbutyl-N-(3-pyridyflamino~carboflylmethyll-pyrrolidifle-3-carboxylic The compound of Example 531A was reacted according to the procedures of Example 523, to give the title compound. I HNMR (D6- DMSO, 300 MHz) 8 0.80 J=6.4 Hz, 3H), 1.15-1.99 (in, 2.59 (in, 1H1), 3.05 (in, 2H), 3.26 (mn, 3.49 (in, 2H), 3.56 J=7.1 Hz, 3.73 (s, D 6.00 211), 6.80 (in, 3H1), 6.85 J=8.1 Hz, 1IH), 6.98 (in, 2H1), 7.04 (in, 1H), 7.41 (dd, J=1. 4.7 Hz, 7.58 (in, 8.36 (bs, 8.54 (bs, 1H), 12.24 (bs, MS (DCI/NH3) at We 532 Anal calcd for C30H33N306-0-1 H3P04: C, 66.55. H, 6.20. N, 7.76. Found: C, 66.59; H, 6.06; N, 7.60.

Example 532 trans. trans-2-(4-Methoxyghenyfl-4-(1 butyl-N-(3-aminonethylhenyl)amino~carboylmlethyll-Qyrrolidine-3carboxylic acid Examplie 532A N-butyl-N-(3-hydroxymethylghenyl)ainine To a solution of 3.69 g (30 mmol) of 3-amino benzyl alcohol in ml DMSO was added 3.78 g (45 minol) solid NaHCO3 and 2.91 ml (27 inmol) 1-bromobutane. The reaction was allowed to stir at 50 '0 for WO 99/06397 PCT/US98/15479 00 O -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.

oo Example 532B N-butyl-N-(3-hydroxvmethylDhenvl)-bromoacetamide 00 0 To a solution of 3.42 g (19.2 mmol) of the compound of Example N 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to O0C; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion.

The reaction mixture was allowed to stir for 5 hours at O'C and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3P04, water, and brine.

Example 532C Ethyl trans, trans-2-(4-MethoxvDhenvyl-4-(1.3-benzodioxol-5-yli-l- [(N-butyl-N-(3-chloromethylphenyl)amino)carbonylmethyll-pyrrolid in e- 3-carboxylate According to the procedure of Example 523C, N-butyl-N-(3hydroxymethylphenyl)-bromoacetamide was coupled with ethyl 2-(4- Methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate.

The crude product (129 mg) was dissolved in 0.5 ml of DMF and cooled to 0°C; 19 mg of LiCI was added, followed by 85 pl 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.

WO 99/06397 PCT/US98/15479 00 S-480- Example 532D Strans, trans-2-(4-Methoxyphenvll-4-(1.3-benzodioxol-5-vyll-r

N-

butyl-N-(3-aminomethylDhenvylaminocarbonylmethyl-Dvrrolidine-3carboxylic acid oo 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, N 6.5 eq) of sodium azide. The resultant solution was heated at 115 °C o for 3 hours. Water was added, and the mixture was extracted with S EtOAc. The organic extracts were washed with fater and brine, and dried over Na2SO4.

Example 532E trans, trans-2-(4-Methoxvyhenyl)-4-(1.3-benzodioxol-5-yll-(Nbutyl-N-(3-aminom ethyl henvylamino)carbonylmethyll-Dyrrolidine-3carboxylic 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, 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 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 (CD3OD, 300 MHz) 8 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

(M+H)

Anal calcd for C32H37N306*4.2 TFA: C, 46.72; H, 4.00; N, 4.05.

Found: C, 46.66; H, 4.06; N, 4.00.

WO 99/06397 WO 9906397PCTIUS98I1 5479 00 -481trans, trans-2-(4-Methoxyphenyfl-4-( 1.3-benzodioxol-5-ylr-1-r(N-! butyl- N-(3-tri methylam moni om ethyl phenyflamino)Qarbonylmethy1- 00' pyrrolidine-3-carboxylic acid To a stirred solution of 0.128 gm of the compound of Example N- 532C in 0.5 ml methanol, 0.25 ml of an aqueous solution of 00 trimethylamine was added. The mixture was allowed to stir at room I temperature under nitrogen atmosphere for 4 hours. IN 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. I H NMR (300 MHz, D6- DMS0) 8 0.83 J=7 Hz, 3H), 1.15-1.40 (in, 4H), 2.62 2H), 3.35 (s, 9H), 3.40-3.80 (in, 10H), 4.47 2H), 6.00 J=3 Hz, 2H), 6.75-6.90 (in, 3H), 7.25-7.37 (in, 2H), 7.45-7.60 (in, 3H). MS (DCI/NH3) at m/e 602 Example 534 (2F.3R.4S)-2-(3-Fluoro-4-methoxyghenyl)-4-( 1.3-benzodioxol-5-yli 1- (N ropyl- Npentanes uIf onyl amino) ethyl-pyrroli dine-3-carboxylLc Examle 54A Ethyl (3-f Iu oro-4 -m othoxy)ben zoyl 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 OC, and a solution of 25 g of 3-fluoro-4methoxyacetophenone 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 HCl 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 WO 99/06397 PCT/US98/15479 00

O

-482is dried over Na2SO4 and decolorized with charcoal to give 34.5 g (97%) of the title compound.

Example 534B oo Ethyl 2-f3-Fluoro-4-methoxvDhenvl-4-1.3-benzodioxol-5-ylpyrrolidine-3-carboxylate oo 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; 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 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 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.

WO 99/06397 PCT/US98/15479 00 S-483- ExamDle 534C Ethyl (2R.3R.4S)-2-(3-Fluoro-4-methoxvDhenyl-4-(1.3-benzodioxol- 5-yl-Dyrrolidine-3-carboxylate oo 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 0 anhydride (9.30 g, 42.7 mmol). After stirring 2 hours at room N0 temperature, the solution was concentrated in vacuo the residue was 0 dissolved in 50 ml ethanol and treated with a solution of 3.75 g sodium N 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 g acetic acid; the mixture was stirred until a solid formed. The solid was filtered, washed with water and dissolved in methylene chloride. After drying with sodium sulfate, the solution was concentrated and the residue crystallized from 1:1 ether:hexane to get 15.99 g of product, m.p. 200-203 (90% yield). The crude acid was suspended in 80 ml ethyl acetate and treated with 4.00 g (33.1 mmol) of (S)-(-)-a-methylbenzylamine. After heating to dissolve the acid, ml of ether was added. Scratching with a glass rod caused the product to crystallize. The solids were filtered and washed with ether-ethyl acetate solution to give 8.22 g (81% yield based on 50% maximum recovery) of salt, m.p. 165-168 0 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 52 0

C.

After concentrating in vacuo, the residue was combined with toluene and stirred with potassium bicarbonate in water for 30 minutes. The toluene was separated, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel, eluting with 33% hexane-67% ethyl acetate to get 6.9 g of the resolved amino ester.

WO 99/06397 PCT/US98/15479 00 S-484- SExample 534D Ethyl (2R.3R.4S)-2-(3-Fluoro.4-methoxyDhenvyl- 4 -(1.3-benzodioxol- 1- 2-(N-DroDvlaminoethyl-pyvrrolidine-3-carboxylate oo The compound of Example 534C was dissolved in 1,2dibromoethane 10 mL per 1 g of starting material 0 diisopropylethylamine (1 mL per 1 g of starting material and Nal 100 00 mg per 1 g of starting material) were added, and the mixture was Sstirred at 100°C for 1 hour. Toluene was added, and the mixture was S 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 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 amine. The residue was dissolved in heptane and filtered to remove a small amount of insoluble material. Evaporation of the solvent gave the desired product (86-93% yield), which was used for the next step without further purification.

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 OC 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 OC 0.5 mm Hg) to give a clear oil, 61% yield.

WO 99/06397 PCT/US98/15479 00 S-485- Example 534F (2R.3R.4S)2-(3-Fluoro-4-methoxyohenyl)- 4 -(1.3-benzodioxol-5-ylv1- (2-(N-Drooyl-N-Dentanesulfonylaminoethyl)-Drrolidine-3-carboxylic acid 00 The compound of Example 534D (200 mg, 0.43 mmol) was S dissolved in 5 mL of CH3CN; 110 mg (2 eq) of N,N- 00 diisopropylethylamine and 72.8 mg (1.2 eq) of 1-pentanesulfonyl 0 chloride were added sequentially, the resultant solution was allowed N to stir at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc. The solution was washed with saturated NaHCO3 solution, 1N H3P04, and brine, dried over Na2SO4 and evaporated to give a yellowish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexane to give 220 mg of product This ester was dissolved in 5 mL of EtOH, to which was added NaOH (46 mg, 3 eq) solution in 2 mL of H20. This mixture was stirred for 3 hours at room temperature. The solution was -concentrated in vacuo using low (<400C) heat. Water (10 mL) and ether (50 mL) were added; the ether layer was extracted with 5 mL of water. The combined aqueous mixture was back-extracted with ether and then neutralized with acetic acid. This solution was extracted twice with ether. The ether was dried (Na2SO4) and concentrated in vacuo. EtOAc (1 mL) and ether (1 mL) were added to dissolve the product, and hexane was added dropwise to produce a white solid. The solid was collected and dried in vacuo to give 125 mg of the title compound.

Example 534H (2R.3R.4S)-2-(3-Fluoro-4-methoxyphenvl4-( 1.3-benzodioxol-5-ivl) (2-(N-Dropyl-N-Dentanesulfonvlaminoethyl-Dvrrolidine-3-carboxy l ic acid, hvdrochloride 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 WO 99/06397 PCT/US98/15479 -486material is stirred with ether overnight to give a white powder, which is collected by filtration and dried overnight in vacuo at 60 Yield Example 535 The compounds in Table 3C may be prepared using methods presented in the above Examples.

Table 3C.

2 -T1 WO 99/06397 PTU9/57 PCT/US98/15479 -487 I I Nyr N9 C11 WO 99/06397 PCT/US98/15479 488.

WO 99/06397 PCTIUS98/1 5479 489 WO 99/06397 WO 9906397PCTIUS98/I 5479 00 -490- 26 00 000 27 28 WO 99/06397 PCTIUS98II 5479 -491- WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -492- 00 42 43 00

N

44 sCOOH 46 47

H

2 N&N *.aCOO 48 49 WO 99/06397 WO 9906397PCT/US98/15479 00 -493- 51 00 00 52 53 *4ICOOH 54 NjrevCOOH

H

2

N

56 57 WO 99/06397 WO 9906397PCTIUS98/I 5479 494- 59 61 *0 64 WO 99/06397 WO 9906397PCTIUS98/I 5479 495 66

-N

68 WO 99/06397 WO 9906397PCT/US9815479 00 -496- 74 00 000 76 77 H NNgN .,COOHN 78 79 N COOH 81

*"COOH

WO 99/06397 PCT/US98/15479 -497- 82 :~8Nr 88 89 -Th' WO 99/06397 WO 9906397PCTIUS98/15479 00 -498- 91 00 00 92 93 N

,ICOOH

94 L CCCOOHI WO 99/06397 499 00 98 99 .00OOH H2N C 00 00 100 101 C0 102 103 PCTIUJS98II 5479 10410 105 WO 99/06397 PTU9/57 PCT/US98/15479 00 00 00 500 106 108 109 110 11213 113 WO 99/06397 WO 9906397PCT/US9S/15479 501 114 115 ~o-Nr' 116 117 118 119 12011 121 WO 99/06397 WO 9906397PCT/US98/15479 502 122 123 124 125 126 127 N,1 128 129 WO 99/06397 CIS8I57 PCTIUS98/15479 130 1:N 132 503- 131 133 134 135 13613 137 WO 99/06397 WO 9906397PCT/US98/I 5479 00 .504 138 139 140 142 144 145 WO 99/06397 WO 9906397PCTIUS98/I 5479 00 -505- 146 147 00 N. )N

C

00 148 149 0 CH 150 151 0 CH b 152 153

CH

3

C

WO 99/06397 WO 9906397PCTIUS98II 5479 506- 155 154 156 157 157 159 160 WO 99/06397 WO 9906397PCTIUS98/1 5479 507 162 163 00 00 164 165 166 167 I 16816 169 WO 99/06397 WO 9906397PCT/U598/I 5479 508 170 00 00 Noo k ko 172 173 174 175 17617 177 WO 99/06397 Pi1S8157 PCr/US98/15479 00 -509- S 178 179 00 sCOOH i2 000 00 182 183 18418 185 WO 99/06397 PCTIUS98I1 5479 -510- 186 wCOOH 188 189 190 H2N 0 0 191 192 193 WO 99/06397 WO 9906397PCT/US98/15479 -511- 194 195 196 197

N

198 199 200 201

I

WO 99/06397 PTU9/57 PCTIUS98/15479 -512- 203 202 HO, I 204 205 206 207

.,N

20820 209 WO 99/06397PCUS8157 PCTIUS98/15479 -513- 210 211

-I

212 213 214 215 21621 217 WO 99/06397PCIS8 47 PCT/US98/15479 -514- 218 219 NrZ 220 221 222 223 224 225 WO 99/06397 WO 9906397PCTIUS98/1 5479 -515- 226 227 N~Th 228 229 230 FyNrt

CH

232 231 233

H

2

N~N$

0 WO 99/06397 WO 9906397PCT/US98/15479 00 -516- 234 235 00 00 0 O

CH

236 237 I No ,COOH HW 0

CH

3 238 239 0 CHg-j 240 241 Ik %N -iOOH WO 99/06397 WO 9906397PCTUS9BII 5479 -517.

242 243 00 00 244 245 246 247 24824 249 WO 99/06397PCIS/157 PCT/US98/15479 -518- 250 251 252 253 254 255 25625 257 WO 99/06397 PTU9157 PCTIUS98/15479 -519- 258 259 260 261 262 263 264

N*

265 WO 99/06397 PCT/US98I15479 520- 266 268 267 269 270 ,NI-r i 272

,N+

I

271 H2N-Vcr I 27 WO 99/06397 WO 9906397PCTIUS98/15479 00 c-I -521- 274 275 00 .'ICOOH 000 0 N 276 277 C jr

'COOH

0 0 CH j CF 278 279 H2N Kj. 4'COOH ,oo 00 0 CHi 280 281 WO 99106397 00 282 00 00 PCTIUS98/I 5479 522 283 284 285 286 287 H2N%%ON.

28828 289 WO 99/06397 WO 9906397PCTIUS98II 5479 00 -523- 290 291 00 0 4'COOH 00I 000 292 293 H N -#.~COOH HN,, 294 295 296 296 297 WO 99/06397 WO 9906397PCTIUS98/15479 524 298 299 300 301 302 I -siCOOH 304 303 305 H~NC C- N WO 99/06397 PTU9/57 PCT/US98/15479 00 -525- 306 307 00 ZH

__CH

3

C.

H2Nua.cOO-00H HAc!3 "aOOH 00 308 309

H

3

H

3 dCOOH COOH 310 311 -33 31231 313 WO 99/06397 WO 9906397PCT/US98/1 5479 00 -526- 314 315 00 c-I.iaCOOH H0 00 c-0 316 317 3000H 0 318 319

CH

3

H-

N

3

HN-,

Y "'NI

'COOH

0

CH

3 WO 99/06397 WO 9906397PCTIUS9815479 527 323 322 H2N%% yI 0 324 326 328 325 327 329

N

+Nooo r

N-

L

WO "/06397 WO 9906397PCTIUS98II 5479 528 331 330 332 333 ~Th 334 335 336 337

HN,,{

WO 99/06397 WO 9906397PCT/UJS98/I 5479 00 -529- 338 339 00 00 340 341 342 341 Ha C OOz 34434 345 WO 99/06397 WO 9906397PCTIUS98/15479 530 346 347 348 349 350 351 352 QOCH 3 N-r N 4COOH 353 HbC 3 {N .COMH 0

-J

WO 99/06397 WO 9906397PCT/US98/I 5479 -531- 354 355

H

2

N-

356 357 358 359 360 QbCH3 361

I

WO 99/06397 WO 9906397PCTIUS98/1 5479 532 362 363 364 365 366 ~bH, HN 0

'COOH

CH

3 368 -'1COOH 0 C H 3 367 0

H

CH

369 WO 99/06397 WO 9906397PCTIUS9SII 5479 00 00 00 533 370 371 372 373 374 9'CH3

'COOH

CH

375 eiCOOH

CH

3 37637 377 WO 99/06397 PTU9/57 PCT/US98/15479 534 378 379 380 381 382 383 *'stCOOH 38438 385

I

WO 99/06397 PCT/US98/1 5479 00 -535- 386 387 000 00 Qb -CH3 N-I N I/QC

O

00 388 389 -aCOOH-,o

Q

390 391 -4~.eCOOH

CO

392 393 WO "/06397 WO 9906397PCT/US98/15479 536 394 395 Ia"~ loThI 396 397 398 399 401 400 I QW WO 99/06397 WO 9906397PCTIUS98/15479 537 403 402 404 405 406 407 40840 409 WO 99/06397 PCTUS98/15479 00 -538'- 00 00 410 411 0 0 0 0 HN .C O O H .400014 CH -~CH 00 412 413 0 0 ;PI iCOOH 0 0 H~~a CH, ,c 414 415 416 417 WO 99/06397 PCT/US98/15479 00 C~ -539- 418 419 00 0 a-%zzt .eCOOH 2 00 0

CH-

3

$C-

420 421

Q

CH

3 422 423 424 425 WO 99/06397 WO 9906397PCT/US98/1 5479 00 -540- 426 427 Q a 00 02 N0N 00 428 429 0 a 0 N COCH H 2 r% AgN .'COOH 430 431 0o JJ.§s ICOHrL 43243 433 WO 99/06397 WO 9906397PCT/US98/1 5479 541 434 Q0 H2 NOO 435 ~N~N(~fN{ 436 437 438 439 44041 441 WO 99/06397 WO 9906397PCTIUS98/1 5479 00 c-I -542- N- 442 443 00 444 445 446 447 03 448 449

Q-

WO 99/06397 WO 9906397PCT/US98/15479 543 450 Zrj1 rN

COOH

452 451 453 454 455 0

CI-

456 457 WO 99/06397 PC/US98/1 5479 .544- 00 00 458

QO

0 CH3 459

CH

3 460 461 462 463

Q

N I

-"COOH

OH -0 464 465 WO 99/06397 WO 9906397PCT/US98/I 5479 545 466 468 467 469 -Th 470 471 472

N,

L

473 .uCOOH WO 99/06397 WO 9906397PCT/US98/15479 546 474 475 476 4$77 478 479

Q

1 0 ~-Th 48048 481 WO 99/06397 PCTIUS98/15479 547- 482 483 485 484 486 487 1 488 -uCOOH 489 WO 99/06397 WO 9906397PCT/US9815479 00 .548ci 490 491 000 00 0.N *cOO 8 COOI 492 493 NueOO N, -NI-C 496 495 N44 CH3V WO 99/06397 PCTIUS98/1 5479 -549- G 498 499 N0N 0 0 0 0 0 00 j C CH 500 501

N'

0 h~cO 0 0

CH

3 jCH 502 503

N

CH

3

H

504 505 r 'N' N4 N/ H~0 WO 99/06397 PCT/US98/15479 00 CI 550c 506 507 000 *"COOH 00

CM

3 508 509 N N 0 CH 510 511 uCOOH

CH

3 512 513 r 0

N

WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -551- 51451 000 I'ICO0HHr- 00 516 517

W-~

0 .lGOOH 518 519 N H 2

N

520 521 N> QN'

(N

WO "9/06397 PCTIUS98/1 5479 00 -552- 522 523

CNZ

00 00 524 525 0 HN r N O

COO

528 529

N

0 528 529 1 0 WO 99/06397PC/S8149 PCT/US98/15479 553 530 531 532 533 535 534 53653 537 WO 99/06397PCIS8149 PCT/US98/15479 554- 538 539 00 00 H2N~%Y 540 541 >rNI~rN 542 543 54454 545 WO 99/06397 WO 9906397PCT/US98/15479 -555 546 547 548 0 CH-j 549

I

H2N,- 550 551 552 553 eNN' WO 99/06397 PCT/US98/15479 00 -556- 554 555 00 -COON 00

CH

556 557 No 558 559 N '0 ,wCOOH 560 561 WO 99/06397 WO 9906397PCT/US98/1 5479 -557- S 562 563 NN4 00 c~ 564 565 566 567 56856 569 WO 99/06397 WO 9906397PCT/US98/I 5479 00 -558c-I 570 571 00N 0 00

.COOH

-COOH

576 573 0

NN

-sCOOH 00 WO 99/06397 PCT/US98/15479 00 00 (N 578 580 559 579 581 582 583 585 585 584 WO 99/06397 WO 9906397PCTIUS98II 5479 560- 586 587 588 589 590 591 592 593 CHPc 0w- r

CH

3V WO 99/06397 WO 9906397PCTIUS98/I 5479 561 594 00 00 595 596 597

CH

3 1 599 598 60060 601 WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -562 602 603 004 COOH0 F~a 00 604 605 *aICOOH0 606 607 N .sCOOH 608 609 0 i~N~~Th -o WO 99/06397 WO 9906397PCTIUS98II 5479 563 611 610 612 613 N 614 615 617 616 WO 99/06397 WO 9906397PCTIUS98/15479 564 00 00 618 620* 619 621 622 623 62465 625 WO 99/06397 WO 9906397PCT/US9815479 565 626 627 628 629 630

FVQCOOH

CH

3 631 633 632 WO 99/06397 WO 9906397PCTIUS98/1 5479 .566 634 635 636 637 638

CH

3 639 64064 641 WO 99/06397 WO 9906397PCTIUS98/15479 00 -567- 642 643 00 N S 00

CH.

3 644 645 646 647 648 649 0 WO 99/06397 PCT/US981 5479 -568- 650 651 00

IC)CO)H

0 00 C- 652 653 N. NrN COOH 654 655 r H2N /'ICOO 0 656 657 WO 99/06397 WO 9906397PCTIUS98/1 5479 569- 658 660 F V O 400 659 0 0 661 662 663 664 665 0

"COOH

WO 99/06397 PCT/US98/I5479 666 668 .570- 667 0 669 670 671 672

-COOH

0 673 WO 99/06397 WO 9906397PCTIUS98/1 5479 571 674 675 676 677 678 679 68068 681 WO 99/06397 WO 9906397PCTIUS98/1!5479 00 .572- 682 XI683

CN']

00 H 2 N- 00 CH1

H

3 c-I 684 685

CH

3 J 0H3 C0 686 687 g' COOH H 2 odic 0 0

CH

3 C H, 688 689 NL~ *..COOH 0 .COI -0 cH WO 99/06397PC I S /1 49 PCT/US98/15479 573- 691 690 692 693 694 695 697 -ouOOH 0" 696 WO 99/06397 WO 9906397PCTILJS98/15479 574 698 699 700 701 702 703 704 0 705 WO 99/06397 PCTIUS98/15479 -575- 706 707 708 H2NOOH 710 712

H*"'COOH

03 709 711 00 713 WO 99/06397 WO 9906397PCTIUS98/15479 714 -576- 715.

717 716 718 719 ~r~~NcI~N rN

"OOH

720 WO 99/06397-57 00-57 722 723 00 0.OO 000 000 .'aOOOH 726 727 PCT/US98/15479 WO 99/06397 PCT/US98/15479 00 .578- 728 729 N I 0 00 q HOOOH 00

CH

3

H

3 Cl730 731 0 0 Nll-~ *NIPO .sCOOH

CH

3

C

732 733 CH ,CO

CHJ

3.H 734 735 0 0 NI N '-tr N IC O* .aCOOH WO 99/06397 W O 996397PC rIUS98II5479 579 736 737 738 H2N,-

-A

739 0

OIOOOH

740 741 742 -4000 '0

OO

0'o0 743 0 WO 99/06397 PCTIUS98/15479 -580- 00 744 745 00 .00 MH 00 0 'OOHW 0 e~O 00 746 747 OOH o 748 749 %rNr I ~j~J -COO 750 751 F)"IIZ1~~ *iCOOH H N- .~0 0 WO 99/06397 PCT/US98/15479 00 -581- G 752 753 00 H2N 00 754 755 H2N,., /c~ 756 757 I ~o rN -uOOOH 758 759 @X0

-CM

WO "9/06397 PCTIUS98/15479 00 -582- 760 761

-A

0

COOH

00 762 763 764 765 0( 0s OO si 766 767

N/A

WO 99/06397 PCTIUS98/15479 00 -583- 768 769 00 00 CM0 2~ N< .~OOH CM 00 C3 CH 3 c~I770 771

N'

772 773 77477 775 WO 99/06397 PCT/US98/15479 584 776 0 0c0

CH

3 778 777 779 780

CO

HG~~~N

782 783 H2NCOOH 0 WO 99/06397 PCT/US98/15479 585 784 785 786 787

H

2

NW

788 790 789 791 WO 99/06397 WO 9906397PCTIUS98/15479 -586- 792 794r< 793 795 4

FV

796 797 yN

L

79879 799 WO 99/06397 PCT/US98115479 S587- 800 8 N 0 ucOOH 802 80O4 804 801 803 805 806 807 N8Th WO 99/06397 WO 9906397PCTIUS98/15479 00 00 00 588 808 809 810 811 813 812 814 9 00

CH

3 815 4 .0e WO 99/06397 PCT/US98/15479 00 -589- 816 817

L

00 00 CH~ CHJ CI 818 819 0 iiCOOH CH3, CH3C 820 821 C0 822 823

H

2 N~ C§ OOH

)N

WO 99/06397 WO 9906397PCT/US98/15479 590 824 825 826 827 828 829 831 830

~NN

WO 99/06397 PCr/US98/15479 00 -591- 832 833 00 0 0 H2.sa OOH 0-iOO 00CC 834 835 "OCOOH0 .CH 836 837 To" -COOH 2 j1000cOH 00 838 839 N $N 00 00 WO 99106397 WO 9906397PCTIUS98/1 5479 840 -592- 841- HOJZ2

CWH

843 0, 842 -Th.

844 845 846 847 N 0 WO 99/06397 WO 9906397PCT/US98/I 5479 593- 848 849 850* 851 852 ~Th *I1~T fls~ ~6L 853 854 855

-COOH

CH

3 WO 99/06397PCIS/149 PCT/US98/15479 00 00 00 594 858

HO,

858 857 859 860

HN%

861 I 862 H2N~~ 863 WO 99/06397 WO 9906397PCTIUS98/1 5479 -595 864 866 N~i 868 865 867 869 870 871 H020.

WO "/06397 WO 9906397PCTJIJS98II 5479 596 873 872 HN NQ 874 875 876 877 878 879 I 61.

WO 99/06397 WO 9906397PCTIUS98/1 5479 597- 880 N rN 882 884 881 883 885 88687 887 WO 99/06397 WO 9906397PCT/IUS99/15479 598 888 889 c 890 0 892 894 891 893 895 WO 99/06397 00 c-I599-- 896 897 .o 00 N2N 000 00 0 898 899 00 tJ0 *.COOH 900 901 PCT/US98/I 5479 90290 903 WO 9"/06397 00 PCT/US98/I 5479 904 905 906 907 908 909 91091 911 WO 99/06397 WO 9906397PCT/JS9815479 -601- 912 913 914 915 916 917 91891 919 WO 99/06397 WO 9906397PCTIUS98/1 5479 602 921 920 N~~NyN "COOH 922 923 Nn 924 925

-I

-N

92692 927 WO 99/06397 WO 9906397PCTIUS98/I 5479 928 00 00 603 929 N r o o I I N C O O H 0 931 0HEIOO 00 930 932 00 934 933

H~N

935 0-N ."COOH WO 99/06397 PCT/US98/1 5479 -604.

936 0 .COO 937 938 939 940 941 <0 <N

"ICOOH

943 942 WO "9/06397 PCT/US98/15479 944 .605- 945

CH

3 947 946 Nt I

-CWH

CH

3 C0 948 .01COOH

CH

3 950 949 0 4,COOH CH -y 951 I I-Th WO 99/06397 PCTIUS98/15479 00 CI -606- 952 953 00

-OCCOOH

00 CH6 3 C3J 954 955 0Y N-40 I 956 957 CH3, CH3 958 959 WO 99/06397 WO 9906397PCTIUS98II 5479 960 607 961

A

0 000 963 962 964 965

"A

0 0 1 ,COOH 967 966 140 H2N WO 99/06397 WO 9906397PCTIUS9815479 -6W8- 968 969 970 971

"A

0 ~C0H 0 972 973 97495 975 WO 99/06397 PCTIUS98/ 5479 976 978 -609- 977 \rTh I-k 979 N~JTh 980 982 983 0 WO 99/06397 00 -610- 984 985 0\00 0 00 986 987 0 .IICOOH 2

-J'

988 989 'rIT~ f 8

"N

PCT/US98/15479 990 991 WO 99/06397 PCT/US98/15479 00 -611- 992 993 00 2--N

H

00

CH

3 1C.- 994. 995 CO)OH dsCOOH CH3-

CH

996 997 99899 999 WO 99/06397 WO 9906397PCT/US98/1 5479 -612- 1000 W~o .iaCOOH 1003 1002 1004 1005 I -o 1006 *d.COOH 1007 WO 99/06397 WO 9906397PCTIUS98/1 5479 -613- 1009 1008 H2O 1010 1011 1012 1014 1013 I ~OOH 1015 0L NC-,00 WO 99/06397 PCTfUS98/15479 00 c~KI -614.

__1016 1017 .W OOH -uN COc 00 1018 1019 *"'GOH "COOH 1020 1021 1022 1022 1023 WO 99/06397 00 -615- 1024 1025 00 ~-T 0 00 1026 1027 N~#Th 1028 1029

VNN

N~ a c 1030 1031 Na~TN PCT/US98/15479 00 00 00 WO 99/06397 WO 9906397PCT/U598/I 5479 616- 1032 1033 1034 1035 1036 1037

CH

3 -03 1039 1038 WO 99/06397 WO 9906397PCT/US98/I 5479 1040 0

CH

3 1042 0

CH

3 1044 -617- 1041

H

2 NN~Nr *."COOi CHt 3 1043 0

CH

3 1045 1046 1 047 H9N"" I WO 99/06397 00 -618- 1'048 1049 00 uOHc 00 11051 1050 -*C ~F O 00 1052 1053

H

2 N0

ICOOH

11055 1054

P~VN~N

PCT/US9/1 5479 WO 99/06397 WO 9906397PCT/US98/1 5479 -619- 1056 1058 1060 1057 1059 1061 1062 16 1063 WO 99/06397 WO 9906397PCT/US9SII 5479 1064 620 1065

UCOOH

1067 1066 1068 1069

.NN

N )rN

ICOOH

0 1070 17 1071 WO 99/06397 00 -621- 1072 1073 000 N1074 1075 N r

ICOOH

0 0 1076 1077

I"COH

1078 1079 NYp**l PCTIUS98/1 5479 WO 99/06397 WO 9906397PCT/US98/1 5479 1080 1082 622 1081

.COH

CH

1083 1084 Nr

N."COOH

CH

3

IW

1086

H

2 N"

U.COOH

0 0

CH

3 0j 1085

N

IICOOH

1087 N N I mcN WO "/06397 WO 9906397PCT/US98/I 5479 .623 1088 1089 00 00 1090 1091 1093 1092 1094 19 1095 WO 99/06397PCIS8I57 PCTIUS98/15479 624 1096 1097 1098 1099 1100 1101 I 1102 1103

-I

WO "/06397 PCT/US98/15479 00 -625- S 1104 1105 >~y~yN 00 1106 1107 H2N iJCCK)H

.,COOH

1108 1109

-N

",COOH *Ccx:O* 00 F -J 1110 11 -N

N

H O N N "'OOOH

*ICOOH

00

C

WO 99/06397 00 -626- 1112 1113

-N

00 CI 1114 1115

-N

0 0 1116 1117

-N

aCOOH 1118 1119 N

N

s.COOH r PCTIUS98/I 5479 WO 99/06397 WO 9906397PCT/US98/I 5479 -627- 1120 1121

N

NscO

H

2

N

ci 1122 1123

-N

0 v'COOH 0 1124 1125 1126 12 1127 WO 99/06397 WO 9906397PCT/US98/1 5479 628 1128 1129 I

N'

1130

-N

"-ICOOH

0

CH

3 1132

-N

I 6 "sCOOH

CH-

1134 1131 1133 1135 ~-Th WO 99/06397 WO 9906397PCTIUS98II 5479 629 1136 1137 1138 1139 1140 1141 1142 1142 1143 WO 99/06397 PCT/US98/I 5479 -630- 1145 1144 1146

-N

ICOOH

1147 1148 1149 1151 H2NOOO- 1150 WO 99/06397PCIS8I57 PCTIUS98/15479 00 00 00 631 1152 1153 1154 1155 1156 1157 1158 1159 WO "/06397 WO 9906397PCT/US98/1 5479 632 1160 1161 1162 1163 ~Th 1164 1165 1166 16 1167 WO 99/06397 WO 99/06397PCT/7US9815479 633 1168 1169 1170 1171 1172 1173 1174 17 1175 I %.Olls le I WO "/06397 WO 9906397PCTIUS98/1 5479 -634- 1177 1176 1178 1179 ~-Th

NC--,

1180 1181 1182 18 1183 WO 99/06397 WO 9906397PCTJUS98/1 5479 -635 1184 1185 1186 1187 1188 1189 1190 19 1191 WO 99/06397 PCT/US98/1 5479 00 -636.

c-I 1192 1193 c-I 00 OH 0 00 1194 1195

OOH

NlC000

"COOH

1196 1197

-N

H2N-~NO-Nr 'COOH 1TI~N *s 1198 1199 i"-N WO 99/06397 PCTIUS98/1 5479 -637- 00 cI 1200 1201 G 0N 0 tCOOH 0 .100 00 00 1202 1203

N-

1204 1205

IN

N

0 COH ICOOHi 0 0 1206 1207

CHO

N-

CH

HOOw 0 Ll tV2L L LU

OLEL

IO I

U-

I-

8O--A 00 6LVS!/86SfW1:d L~O6 L600/66 OM WO 99/06397 WO 9906397PCT/US98/1 5479 00 -639- 1216 11 00 .na000H H 2 NN<" )N 0 CH3

CH

3 0 1218 1219 H 2 N N I r N ,C O O H CH CH 3 d 1220 1221 .aCOOH CH~ C 1222 1223

-N

0 "SCOTH WO 99/06397 WO 9906397PCT/US98/I 5479 640 1224 1226 1225 1227 1228 rd%~ *'COOIH 0 1230

-N

.sCOOIH 0 1229 1231 WO 99/06397 WO 9906397PCT/1US98/1 5479 00 -641- 1232 1233

-N

00 N COOH 00 cI 1234 1235 N NNN 0 -"uCOOH 1236 1237 NN N 1238 1239

I

WO 99/06397 WO 9906397PCTIUS98/1 5479 -642- 1240 1241 1242 1243 1244 1245 1246 14 1247 WO 99/06397 WO 9906397PCT/US9815479 00 -643- 1248 1249 00 0 C--a 00 NI 1250 1252 1254

-)CO

WO 99/06397 WO 9906397PCT/US98/I 5479 644- 1257 1256 1258 1259 -yN4 1260 1261 1262 1263 WO 99/06397 WO 9906397PCT/US98/1 5479 00 -645- 1264 1265 00 ~N .,ICOOH 00 I

M

00 1266 1267

.,COOH

0

.'I

CH-

1268 1269 ~'IC0N 1270 17 1271 WO 99/06397 WO 9906397PCTIUS98/1 5479 -646- 1273 1272 00 00

COOH

CH

3 1274 1275 -i 1276

-TA

1277 0 1279

IA"

1278 WO 99/06397 PCTUS98/1 5479 00 -647- 1280 1281

N

CKIM

00 00 1282 1283 ~N *.1iCOOH 1284 1285 N TN N0A 0UOO 1286 1287 WO 99/06397 WO 9906397PCTIUS98/1 5479 -648- 1289 1288 1290 1291

HQ,,.

1292 1293 1294 19 1295 WO 99/06397 PCT/US98/15479 649 1296 1298 1300 1297

I

1299 Li 1301 1302 xCAOOH 1303 WO 99/06397 WO 9906397PCr/US98/1 5479 -650- 1304 F r ICOH 1305 1306 1307 1308 H2N%%.N, 1309 %g N O

CH

3 i 1310 1311

CH

3 WO 99/06397 PCT/US98/15479 00 -651- 0 0 1312 1313 0COOH 00 CH3 00 0 1314 1315 Sn 1316 1317 1318 1319 WO 99/06397 WO 9906397PCTIUS98II 5479 00 -652- 1320 1321 00

-XO

0 -a 00 1322 1323 N 0

*.COOH

0 1326 1327 Wo 99/06397 WO 9906397PCTIUS98/1 5479 653 1329 1328 1330 1331 1332 1333 1334 13 1335 WO 99/06397PCUS/I59 PCT/US98/15479 00 .654- S 1336 1337 00 Hoo- -XOH 00 0 1338 1339 N *a@COOH 1340 1341 1342 14 1343 WO 99/06397PC/S8147 PCTIUS98/15479 00 -655- 0- 1344. 1345 00 m~~~COOH j jj .61 c- 0 00 1346 1347 *siCOQH I *81nCOOH

CH

3 1348 1349 1350 1351 WO 99/06397 WO 9906397PCTIUS9815479 656 1352 00 CH j 1353 N .COCH N 0 CH 1354 1355 1356 1357 1358 1359

N~T

+NKIr I WO 99/06397 WO 9906397PCTIUS98/1 5479 1360 657 1361

CH

3 1363 1362 1364 1365 HO ,_I -Th 1366 16 1367 WO 99/06397 WO 9906397PCTIUS98/I 5479 658- 1369 1368 1370 1371 1372 1373 1374 ~N r 1375 WO 99/06397 PCT/US98/15479 00 -659- 1376 1377 00 r oL 00 c- 1378 1379

N.

*"COOH

0 1380 1381

N

1382 1383

,-N

WO 99/06397 WO 9906397PCT/US98/15479 660.- 1384 1385 1386 1387 1388

"'ICOOH

0 1390

N

H2~

NN

1389

N~T

1391

N

WO 99/06397 WO 9906397PCTIUS98I1 5479 00 00 00 -661- 1392 0* -UCOOH

CH

3 1394 1393 1395 N- W ohI 0'

HQ~

1396 1397 1398 1399 ,NZ, N, WO 99/06397 1400 PCTIUJS98/15479 662 1401

*"'COOH

00 CHa 1403 1402 1404 1405 1406 1407 WO 99/06397 WO 9906397PCTIUS98/15479 663 00 00 00 1408 1409 1410 1411

H

2

NN~N.

1412 1413 1414 11 1415 WO 99/06397 664 00 c-I1416 1417 1 6 *s'COOH 00 00 1418 1419

*'ICOOH

1420 1421 *'iCOOH 1422 1423 PC'riUS9/1 5479 WO 99/06397 WO 9906397PCT/US98I1 5479 665 00 00 00 1424 1425 1426 1427 1428 1429 1 430 13 1431 WO "/06397 WO 9906397PCTIUS98/15479 666 1432 1433 1434 1435 1436 1437 L uCOOH

OH

3 j 1438 13 1439 WO "/06397 WO 9906397PCT/US98/I 5479 00 .667- 1440 1441 N

N

00 ON~ *smCOOH *.aCOOH 000 00CH 3

CH

1442 1443 N N -s0=H $N 4COOH.

CH C 1444 1445 1446 14 1447 WO 99/06397 WO 9906397PCT/US98/I 5479 00 -668 1448 1449 009 000 iCH 3

CH

3

X

1450 1451 0 CH -j CH 3 1452 1453

)N

NN

NN

.uCOOH ~~oi WO 99/06397 WO 9906397PCTIUS98/1 5479 00 .669- 1456 H2NN 00 H2" )o"N-COOH N .%.N.CON 0 00 1458 1459 c~N N NrN.COOH 6r *..C00H 1460 1461 COOH NaCOl HzN.-'CAX> 1462 16 1463 WO 99/06397 WO 9906397PCT/US98/I 5479 670 1464 1465 1466

.N

*aCOOH 1470 1467 1469 6 L 1471 WO 99/06397 PCTIUS98/15479 00 -671- S 1472 1473 00 0.~c~ 1474 17 0 1476 17 1478 1 7 1479 00 00 00 WO 99/06397 WO 9906397PCTIUS98/1 5479 672 1480 1481 1482 1483 1484 1485 Nr 1486 18 1487 H -r I WO 99/06397 WO 9906397PCT/US98/1 5479 673 1488 0 1489 1490 1491 1492 1493 1494 1495 H N >C WO 99/06397 WO 9906397PCTIUS98/1 5479 674 1496 1497 1498 QuCOOH 1599 1500 1501 1502 1503 WO 99(06397PCIS8 57 PCT/US98/15479 00 -675- 1504 1505 00 IN .,cOOH H1-4 0 00 1506 1507

INN

Io~ I *.COOH 1508 1509 N 1 ~.saaCOOH N 1510 11 1511 WO "/06397 WO 9906397PCTIUS98/15479 00 8 -676- 1512 1513 c-I CH c-II 00 c-I1514 1515

OH

1516 1517

CH

3

H

2 N* N 'rN iCOOH

HN,,

1518 1519

OHN

I

WO 99/06397 WO 9906397PCT/US9815479 677 00 00 00 1520 H2N, 1522 1521 1523 152 1525 1526 12 1527 WO 99/06397 WO 9906397PCT/US98/15479 00 -678- 1528 1529

CH

00 uCOOH' 00 CH 3 l 1530 1531

CH

3

C

Y r N C O H P 4 N N uCOOH H 2 N

CH

3 CHJ3 1532 1533

CH

H2N%. '-tr JCO6 0

-CO

1534 13 1534 WO 99/06397 WO 9906397PCT/US9815479 679 1536

CH

0 -1--ON.COOH

CH

3 1538 1537 1539 1540

CH

3 b IN y -4COOH

CH

1542

CH

3

COOH

1541 1543 N CH ~OA

.COOH

WO 99106397 WO 9906397PCTIUS98/15479 00 -680 S 1544 1545

C~H

00 0 ONCOOH 00 1645 1647 N~r *"eOOOH 2,.

1548 1549

CH

K~-ThJ.

.N N 1550 1551 WO 99/06397 PCT/US98/15479 00 -681- 1552 C31553

H

.uiCOOH %g -o~CO)OH 00 0/ 00 1554 1555

CH

3

CH

U~COOH H2* N SCOOH 1556 1557 1558 1559 WO 99/06397 WO 9906397PCTIUS98/1 5479 1560 .682- 1561 sK;OOH 1563 1562 1564 1565 cr0 1566 16 1567 WO 99/06397 WO 9906397PCTIUS98/15479 -683- 1569 1568 .111 1570 c.0 1571 CN0

N~

*."ICOOH

1572 1573 1574 1575 0

N,

WO 99/06397 WO 9906397PCT/US98/15479 -684- 1576 17 000 000

CH

c-I1578 1579 0N 0

CH

3 1580 1581 T II "gCOOH 00

CH

1582 1583 0 .snCOH Qcr WO 99/06397 WO 9906397PCT/US98/I 5479 00 c-I -685- 058 1585 0-'COOH IIKX)OH 00 H 00

OH

3

CH

3 c-I1586 1587 cr .COOH 0 IpUOOH 1590 159 a~ 0 Qr0 pr NOHH,, r

CO

H2 NA N 0 0 WO 99/06397 WO 9906397PCT/US9S/1 5479 686 1592 1593 1594 1595 1596 1597 1598

KY

1599 cy0 WO 99/06397 WO 9906397PCT/US9815479 687 1601 1600 1602 1603 1604 1605 1606 1607 WO 99/06397 WO 9906397PCTIUS99/15479 00 -688 c-i1608 1609 00 ICH __OO K4~C=OH 00 N N

ON

00 1612 1613 1614 11 1615 WO 99/06397 WO 9906397PCTIUS98/I 5479 689 1616 1617 1618 1619 1620 1621 1622 12 1623 WO 99/06397 WO 9906397PCTIUS98/1 5479 00 -690- 1624 1625 00 0 3 0C00 c-I c-I1626 1627 HI b-- 1628 1629

CH

3 0 N~y7N -flOOH CHt 3

XI

1630 1631

H

2 ~N IrN

*"-COOH

-0 WO 99/06397 PCTIUS98/1 5479 -691- 1632 1633 CKIz

CH

3

OOH

00 1634 1635 ICOOH0 0t

COOO

1636 1637 H2NN N Nt HJ4,_ 0 1638 1639 CH3O WO 99/06397 WO 9906397PCTIUS98/1 5479 692.

1641 1640

H

2

N~,N%

CH

3 g'"=CH 1642 1643 00%

N

1644 1645 3

C

H2N OA{N' 1647

CHPO-

1646 WO 99/06397 WO 9906397PCT/U598/1 5479 00 .693- 1648 1649

CH

3 0 N 00 c-I1650 1651 -hCH§p O.iCOOH 1652 1653 1654 15 1655 WO 99/06397 WO 9906397PCT/US9815479 00 -694- 1656 1657

N

1658 1659 1660 1661 1662 16 1663 WO 99/06397 WO 9906397PCT/US9815479 00 -695- S 1664 1665 00 CH.00 000 CH-, 3 1666 1667

C

3 1

_ICOO

0

CH

3 1670 1671 Z L.

WO 99/06397 PCT/UJS98/I 5479 00 -696- 1672 1673 00 N~m CH 3 0 00 Nr

.I'COOH

00

CH

c-I1674 1675 N-N~ 0 CHo 3 1676 1677

CH

3 0

.COOH

0 CH 0 1678 1679

OH

2 F Nr HQaOO WO 99/06397 WO 9906397PCT/US98/I 5479 697 1680 1681 1682 0 1683 1684 1685 1686 168 1687 WO 99/06397 PCTIUS98/1 5479 00 -698- 1688 1689

CM

2 CH3O 00 00 C- 1690 1691 *4COOH .NyO 1692 1693 ."mCOOH

N):

1694 1695 N *.sCOOH

N

WO 99/06397 PTU9/57 PCTALJS98/15479 -699 1696 1697 1698 1699 1700 1701 1702 1703 WO 99/06397 PCTIUS98/1!5479 00 -700- 1704 1705 00 uCOOH 00 1706 1707

N

0 I

CH

1708 1709 0 *'uiCOOH0 CH3

CH

3 0 1710 1711 WO 99/06397 WO 9906397PCTIUS98/I 5479 -701- 1712 1713 1714 1716 1715

H

2 N11 rCCIO 00

CH

3 1717 oeI 1718 11 1719 WO 99/06397 WO 99/697CTIUS98/1 5479 .702 1720 1721 1722 1723 1724 1725 1726 12 1727 00 00 00 WO 99/06397 WO 9906397PCTIUS98/1 5479 -703 1728 1729 1730 1731 1732 1733 1734 13 1735 WO 99/06397 WO 9906397PCT/US98/15479 704 1736 1738 1737 1739 1740 1741 H2N-" l 1742 H '0 0

*-'COOH

1743 *.sCOOH 0 0 WO 99/06397 PCTIUS98/15479 00 -705- 1744 1745 .0 Hr' 00 .11COH 2N^, N "COO 0 0 000 cl 1746 1747 ~NNII'? -b H to HT HH NoN N~ -oCC4100 H 0~rN OOH 1750 1751 090 O C*01 WO 99/06397 WO 9906397PCT/U59815479 706 1753 1752 1754 1755 -Th 1756 1757 1758 1759 WO 99/06397 WO 9906397PCT/US98/15479 707 1761 1760 1762 1763 1764 1765 1766 16 1767 WO 99/06397 WO 9906397PCTIUS98/1 5479 708 1768 1769 1770 1771 1772 H 1-

H

2 N cI ~N "'COOH 0 1773 1N.

0 0 1774 17 1775 WO 99/06397 WO 9906397PCT/US98/I 5479 709 1776 1778.

1777 1779 1780

H.

H I H2N IR:

CA)OH

1781 H 0.CO WO 99/06397 PCT/US98/15479 -710- 00

O

SExample 536 S12S.3R.4S1-2-(2.2-Dimethylpentyl).4-(7-methoxy-1.3-benzodioxol-5- Sv-l-(N.N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic ExamDle 536A oo Ethyl 5.5-dimethyl-3-oxooctanoate SEthyl 3,3-dimethylhexanoate was prepared using the general o0 procedure of Cahlez et al., Tetrahedron Lett., 31, 7425 (1990). To a Ssolution of 63.8 g (370 mmol) of this compound in 400 mL of ethanol, Cl 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 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 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), 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 WO 99/06397 PCT/US98/15479 00

O

S-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 oo ether, to give'51.8 g of a yellow solid.

O Example 536C N Ethyl trans. trans-2-(2.2-DimethylDentyl-4-(7-methoxv-1.3oO benzodioxol-5-vyl-Dvrrolidine-3-carboxylate 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 tums reddish brown, and homogeneous. The solvents were removed in vacuo; the residue was taken up in EtOAc and 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 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 overnight 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.

WO 99/06397 PCT/US98/15479 00 C -712- Example 536D Ethyl r2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxv-1.3benzodioxol-5-yl)-pyrrolidine-3-carboxylate 00 The crude compound of Example 536C (2.0 g) was combined with 4 0 mL of triethylamine in 40 mL of THF; 2.0 g of di-tert-butyldicarbonate 0 was added, and the mixture was stirred at ambient temperature for Ohrs. Solvents were removed in vacuo, and the residue was taken up in S mL of ethanol. Aqueous sodium hydroxide (10 mL of 2.5 N solution) was 0 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 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 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 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, WO 99/06397 PCT/US98/15479 00 8 -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.

00 The ether layer 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 N resultant material was dissolved in 5 mL of TFA and stirred at ambient 00 0 temperature for 1 hr. Solvents were removed in vacuo; the residue was 0 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 [2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxy- yl)-l .(N.N-di(n-butyl)aminocarbonylmethyl)-prrolidine-3-carboxylic acid 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 3 HOnig's base was added, and the solution was allowed to stir overnight 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.

1H NMR (CDCI3, 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), WO 99/06397 PCTIUS98/15479 00 -714- S 3.30-3.42 (in, 3H), 3.72 J 10.5 Hz, I1H), 3.86 J 10.5 Hz, I 3.88 3H), 4.02 J 10.0 Hz, 1H), 4.12 J 16.8 Hz, 1H), 4.29 J= 16.8 Hz, I1H), 4.41 (brm, 1 5.94 1 6.52 J 1.8 Hz, I1H), 6.67 (d, 00 J 1.8 Hz, 1H). MS (ESI) at W/e 533. Anal calcd for C301H 4 BN2O6*0.7 TFA: C, 61.57; H, 8.01; N, 4.57. Found: C, 61.59; H, 8.20; N, 4.63.

00 Example53 r2S.3R.4S1-2-(2.2-Dimethylpentyl)-4-(1 .3-benzodioxol-5-yf- N di(n-butyl)aminocarbonytlmethyl)-pyrrglidifle3-carboxylic acid 0 Ethyl trans. trans-2-(2.2-D Imethylpe ntyl)- 4 -ben zod Io p yr roll dine-3-ca rboaxy late Prepared according to the procedures of Example 536C above, substituting the compound of Example 501 B (5-(2-nitrovinyl)-1 ,3benxodioxole) for 4-methoxy-6-(2-nitrovinyl)-1 ,3-.benzodioxole.

io ~Ethyl r2S3R4S12 (22 Dim ethyl peftyl) 4 (l .3-be nzodi0ool p2yrrolidine-3- arboxylate 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 WO 99/06397 PCTIUS98/15479 00 -715- 2S.3R.4S]-2- Dim ethy-lpentyfl-4- (1 .3-benzodi oxoI- 5-yfl)-1 Ndi(n-butyflaminocarbonylmethyl)-pyrrolidine,-3-carbgxylic aced 00 C* 5 Prepared from the compound of Example 537B according to the procedures of Example 536E. 1HNMR (CDCI3, 300 MHz) d 0.80-0.99 (in, NI 15H), 1.10-1.37 (in, 8H), 1.43-1.58 (mn, 4H), 1.77-1.97 (in, 2H), 3.48-3.12 00 3.60-3.69 (in, 1H), 3.75-3.86 (in, 1H1), 3.95-4.16 (in, 2H), 4.28c-i 4.4 (mn, 2H), 5.94 6.74 J=7.8 Hz, 1H), 6.8 (dd, J=8.1, 1.5 Hz, 0 6.87 J=1.8 Hz, MS (APCI+) mle 503 Example 53 r2S.3R.4S1-2-(2 .2-Diinethylpentyfl-4-( 1.3-benzodioxol-5-yfl-1 propoxy. N- (n-butyl))ami no carbonyl methyl-pyrrolldine- 3- ca rboxyli acid N-Boc-N-butyl-0-allylhydroxylainine .0 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 (BmL) and di-t-butyldica rbon ate (1 0.0g) 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 THIF was removed in vacua and the residue taken up in EtOAc (25 inL, and washed with water (1 x mL), saturated sodium bicarbonate solution (3 x 50 inL), 1 N phosphoric acid (3 x 50 mL), and brine (1 x 50 inL). 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 0 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 0CC. 1-lodobutane (4.1 mL) was added dropwise to the mixture. The reaction was stirred at 000- for one hour, then stirred overnight at room temperature. The THF was removed in vacua and the residue taken up in EtOAc (50 mL) and washed with water (1 x 50 inL, WO 99/06397 PCT/US98/15479 00

O

C -716- S saturated sodium bicarbonate solution (3 x 50 mL), 1N phosphoric acid (3 x 50 mL), and brine (1 x 50 mL). The organic layer was dried with sodium sulfate and evaporated to give a light yellow oil, which was 0 o purified by flash chromatography on silica gel eluting with EtOAc/hexanes to give the title compound as a colorless oil (6.0 g).

0o Example 538B SN-butyl-N-propoxyamine trifluoroacetate D 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 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 0 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.

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 ourification.

WO 99/06397 WO 9906397PCTIUS98/I 5479 -717- 12S.3R 4J-2-(2 .2-Dimethylpentyl)-4-(1 .3-benzodioxol-5-yl)-1 00 propoxy. N-(n-butyl)aminocarbonyimethyfl-pyrrolldine-3-carboxylic c-i The compound of Example 537B was reacted with the compound of 00 Example 538C according to the procedures of Example 536E.

Examle53 r2S.3RAM5-2-(2 .2 -De methyl pentyl)-4-(1 .3-ben zod oxo 1-5-yfl -I propoxy. N-(n-propyi))aminocarbonylmethyl-pyrrolidine-3-carboxylic Exam 3A N-propyi-N-propoxy bromoacetamide Prepared according to the procedures of Example 538A-C, substituting iodopropane for iodobutane in Example 538A.

r2S.3R.4S] Dim ethyl pe ntyl)-4-( 1.3-benzo dio xoi-5-yfl)-1 p2rop oxy. N-(n-p ropy)a m inoca rb ony m ethyl)- pyrrolidi ne-3 -a rboxyiC The compound of Example 537B was reacted with the compound of Example 539A according to the procedures of Example 536E.

WO 99/06397 PPr/S98/1 5479 00 Cl -718- Examole 540 r2S.3R.4SJ-2-(2.2-Dlmethylpentyl)-4-(7-methoxy-1 yl)-1-((N-propoxy N-(n-butyl))aminocarbonylmethyl)-pyrrolidine- I 00 carboxylic acid The compound of Example 5360 was reacted with the compound of C-IExample 538C according to the procedures of Example 536E.

00 Example 541 [2S.3R.4S-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1 yl)-1-((N-propoxy N-(n-propyl )aminocarbonylmethyl)-pyrrolidine-3carboxylic acid The compound of Example 5360 was reacted with the compound of Example 539A according to the procedures of Example 536E.

Example 542 r2S.3R.4S1-2-(2.2-Dimethylpent-3-enyl)-4-(1 .3-benzodioxol-5-yl 1 ((N-propoxy N-(n-butyl))aminocarbonylmethyl)-pyrrolidine-3o carboxylig acid Example 542A trans-Ethyl 3.3-dimethyl-4-hexenoate A mixture of 4-methyl-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 15000 for 7 hr. The product was then distilled under normal pressure (200-220 00) to give 5.0 g of crude ester as a colorless oil.

Example 542B Ethyl trans. trans-2-(2.2-Dimethylpent-3-enyl)-4-( 1 .3-benzodi yl)-pyrrolidine-3-carboxylat The title compound is prepared according to the procedures of Examples 536A and 5360, substituting the compound of Example 542A WO 99/06397 PCT/S98/15479 00 -719for ethyl 3,3-dimethyihexanoate in Example 536A and the compound of c Example 501B (5-(2-nitrovinyl)-1,3-benxodioxole) for 4-methoxy-6-(2nitrovinyl)-1 ,3-benzodioxole in Example 536C.

00 Example 542C Ethyl r2S.3R.4S]-2 Di m ethyl pent-3-e nyl 3-benzodi oxol c v~yl -prroIi d in e- 3- carb oxylate 00 The compound of Example 542B was resolved according to the procedure described in Example 537B.

Example 542D [2S.3R.4S-2-(2.2-Dimethylpent-3-enyfl-4-(1.3-benzodioxol-5-yl)-l- ((N-propoxy. N-(n-butyl))amnocarbonylmethyl)-pyrrolidine-3carboxylic acid The compound of Example 5420 was reacted with the compound of Example 538C according to the procedures of Example 536E.

Example 543 (2S.3R.4S-2-(2.2-Dimethylpent-3-enyl)-4-(1.3-ben ((N-propoxy N-(n-propyl))aminocarbonylmethyl)-pyrrolidine-3carboxylic acid The compound of Example 542C was reacted with the compound of Example 539A according to the procedures of Example 536E.

Example 544 (2S.3R.4S-2-(2.2- Dim ethyl pent-3-enyl) (7-methoxy- 1 .3benzodioxol-5-yl)-l-((N-propoxy. N-(n-butyl))aminocarbonylmethyl)ovrrolidine-3-carboxvlic acid WO 99/06397 PCT/US98/15479 00 -720- Example 44A Ethyl trans. tran&-2-(2.2-Di methyl pe nt-3-enyl)-4-(7-methoxy- 1 .3be nzodi oxo 1-5-yl) -pyrrol *don -3-ca rboxyl ate 00 The title compound is prepared according to the procedures of Examples 536A and 5360, substituting the compound of Example 542A for ethyl 3,3-dimethyihexanoate in Example 536A.

Example 44B Ethyl [ZS.3R.4sj.2-(2.2-Dimethylpent-3-enyfl-4-(7-methoxy. 1.3ne-3-ca rboxylate The compound of Example 544A was resolved according to the procedure described in Example 536D.

Exampl 44C r2S.,3R.4S-2-(2.2-Dim ethyl pent-3-enyfl-4- (7-methoxy- 1 .3benzodioxol-5-yI)-1 -((N-propoxy. N-(n-butyl))am inocarbonylm ethyl)pyrrolidine-3-carboxyliC acid The compound of Example 544B was reacted with the compound of Example 538C according to the procedures of Example 536E.

r2S.3R.4s1-2- (2.2-Di methyl pent-3-enyl) -4-(7-methoxy-1. .3- N-(n-propym)aminocarbonylmethfl)pyrrolidine-3-carboxylic acid The compound of Example 544B was reacted with the compound ot Example 539A according to the procedures of Example 536E.

r2S.3R.45] -2 pyridyl) ethyl) (1 ben zod ioxol-5-yi)- 1 -frMN 4 heptyl-Nl,(2-methyl-3-fluorophenyl1 amino carbonylmethy]pyrrolidine-3-carboxvlic acid WO 99/06397 PCT/US98/15479 00

O

-721- SExample 546A Ethyl trans.trans-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-vllpyrrolidine-3-carboxylate 00 oo The title compound is prepared according to the procedures of Examples 536A and 536C, substituting the compound of Example 519A c for 3,3-dimethylhexanoic acid in Example 536A.

oo 00 SExample 546B Ethyl [2S.3R.4SI-2-(2-(2-pyridyl)ethyl)-4-(1.3-benzodioxol-5-vy)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 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 S chromatography on silica gel eluting with 1/10/10 EtOH/EtOAc/hexanes to 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- WO "/06397 PCT/US98/15479 00 c-i -722- (450 mg) and slower-moving isomers (400 mg). The faster-moving diastereomer (400 mg) was taken up in 6N HCI and heated at refiux overnight. The solvent was evaporated and the residue was taken up in 00 toluene (75 ML) and evaporated. This was repeated two additional times to give a brown solid, which was dissolved in EtOH (5OmL). 4N HCI/dioxane (10 mL) was added and the solution heated at reflux N- overnight. The EtOH was evaporated and the residue taken up in EtOAc 00 which was treated with saturated sodium bicarbonate solution (3x50 c-I mL), and brine (1x50 mL), and evaporated to give a brown solid. Flash chromatography on silica gel eluting with 30% EtOHIEtOAc gave a mixture of products (130mg) which was approximately 70% desired material. This product was carried forward without additional purification.

Exampl 46C r2S.3R.4S-2-(2-(2-pyridyl~ethyl)-4-fl .3-benzodioxol-5-yl)-l 4WrN 4he pty I 44(2-m ethyl- 3-f luo rophenyl)l amino carbonylmethyllpyrrolidine-3-carboxylic acid 0 The compound of Example 546B was reacted with the compound of Example 508E according to the procedures of Example 536E.

Examl 47 [2S.3R.45]-2 Methoxyph enyfl-4-(1 .3 -ben zodi oxol-5-yfl)-1 -r(N -butyl- N-(4-dimethylaminobutyflamino)carbonylmethyll1pyrrolidine- 3 Examl 47A N-butyl-4-hyd roxybutyramide To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 8500 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.

WO 99/06397 PCT/US98/15479 00 -723- SExample 547B eC N-butyl-4-hydroxybutyl chloroacetamide To an ice cooled solution of 3.40 g (91.9 mmol) of LIAIH4 in 90 mL 00 of THF was added 2.4 mL of 98% H2S04, dropwise, with stirring. After S bubbling had ceased, a solution of 4.7 g of the compound of Example 0 547A in 10mL of THF was added. The mixture was stirred at reflux for oo 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 S 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 12S.3R.4S]-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yl- 1 -I(Nbutyl-N-(4-hydroxybutyl)amino carbonylmethyll-Dvrrolidine-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% H3P04 (1 x 25 mL), saturated aqueous NaHCO3 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 WO 99/06397 PCT/US98/15479 00

O

O

-724- S chromatography, eluting with 98:2 diethyl ether: methanol to give of a colorless oil.

00 SExample 547D Ethyl r2S.3R.4SI-2-(4-Methoxvphenvl)-4-(1.3-benzodioxol-5-vly-1l-rN- N butyl-N-(4-bromobutylaminocarbonvlmethyll-Dyrrolidne-3- 0 carboxylate 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 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 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 (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 (2S.3R.4S-2-(4-MethoxyDhenyl)-4-(1.3-benzodioxol-5-yl- 1 -(N-butyL- N-(4-dimethylaminobutylamino)carbonvlmethyl]-pyrrolidine-3carboxylic 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. Ine resuiiant maieriai waa akenl up i. .L WO 99/06397 PCT/US98/15479 00 -725of IA4N NaOH in 5:1 ethanol/water and stirred at ambient temperature NI for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with 1iM HCI mL required). The 00 mixture was extracted with EtOAc the aqueous layer was C\ concentrated in vacuo. The residue was washed 3X with acetonitrile; the combined washes were filtered through Celite and concentrated to N give 596 mg of a white foam.

00 Example 48 r2S.3R.4sJ-2- Di*methylpentyfl)-4 ben zod ioxoI- 5-Yl)- 1 -r(Nbutyl- N-(4-di methyl am inobutyl~a mino) carbonyl methyl]-pyrroli di ne-3-.

cabxlcai Prepared according to the procedures of Example 547, substituting the compound of Example 537B (ethyl [2S,3R,4S]-2-(2,2- D imethyi pentyl)-4-( 1,3-benzodioxol-5-yl)-pyrrol idi ne-3-carboxyl ate) in Example 547C.

Examle54 [2S.3R.4S]-2-(2.2-Dimethylpentyl)-4-(7-methoxy-1 yf)l-r-(N-butyl-N-(4-dimethylaminobutyflami-no'carbonylmethyllpyrrolidine-3-carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 536D (ethyl [2S,3R,4S]-2-(2,2- D im ethyl pentyl)-4-(7-methoxy- 1, 3-benzodioxol-5-yl)-pyrrolidin e-3carboxylate) in Example 547C.

r2S.3R.4sj-2-(2.2-Dimethylpent-3-enyfl-4-(1 .3-benzodioxol-'5-yfl-1 [(N-butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]-pyrrolidine- 3-carboxylic acid Prepared according to the procedures of Example 547, substituting the compound of Example 542C (ethyl [2S,3R,4S]-2-(2,2- WO 99/06397 PCT/US98/15479 00 -726- D Dimet hyl pent-3 -e nyl) (1 benzodi oxol1-5-yi)- pyrrolI!d ine-3carboxylate) In Example 5470.

00 Example 51 C 5 [2S.3R.'4s1-2-(2.2- Dim ethylpent-3-en yfl)4- (7-m et hoxy-1. .3benzodioxol-5-yf)l-r-(N-butyl-N-(4dimethylaminobutylamnoicarbonylmethyl-pyrrolidine-3-carboxylic 00 0 Prepared according to the procedures of Example 547, substituting the compound of Example 544A (ethyl [2S,3R,48]-2-(2,2- Dim ethylpent-3-enyl)-4-(7-methoxy- 1,3-benzodioxol-5-yl)pyrro lidi ne-3-carboxyl ate) in Example 547C.

Exam 52 [2S.3R.4S-2-(2.2-Dimethylnent-3-enyl)-4-(1 .3-benzodioxol-5-yl)-1 N-di(nbutyl)amino)carbonylmethyl]-pyrrolidine-3-carboxylic acid Prepared according to the procedures of Example 1, substituting the o compound of Example 541C (ethyl[2S,3R,4S3-2-(2,2-Dimethylpent-3enyl)-4-(1 ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxylate).

r2S.3R.45]-2-(2.2-Di methyl pent-3-enyfl-4- (7-methoxy- 1.3benzodioxol-5-yl)-1 -r(N.N-di(n-butyl)amino~carbonylmethyI]pyrrolidine-3-carboxylic acid Prepared according to the procesures of. Example 1, substituting the compound of Example 544B (ethyl [2S,3R,4S]-2-(2,2-Dimethylpent-3enyl)-4-(7-methoxy-1, ,3-benzodioxol-5-yl)-pyrrolidine-3-carboxyI 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.

WO 99/06397 PCT/US98/15479 S-727- 0 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 oo E Recetor Preparation of membranes from MMQ cells: SMMQ [MacLeod/MacQueen/Login cell line (prolactin secreting rat N pituitary cells)] cells from 150 mL culture flasks were collected by O centrifugation (1000xg for 10 min) and then homogenized in 25 mL of c- 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and protease inhibitors [3 mM EDTA 0.1 mM PMSF, and 5 g/mL Pepstatin A] by a micro ultrasonic cell disruptor (Kontes). The mixture was centrifuged at 1000xg for 10 min. The supematant was collected and centrifuged at 60,000xg for 60 min. The precipitate was resuspended in 20 mM Tris, pH 7.4 containing the above protease inhibitors and centrifuged again.

The final pellet was resuspended in 20 mM Tris, pH 7.4 containing protease inhibitors and stored at -80 0 C until used. Protein content was determined by the Bio-Rad dye-binding protein assay.

[1 2 5 1]ET-1 binding to membranes; Binding assays were performed in 96-well microtiter plates pretreated with 0.1% BSA. Membranes prepared from cells were diluted -100 fold in Buffer B (20 mM Tris, 100 mM NaCI, 10 mM MgCI2, pH 7.4, with 0.2% BSA, 0.1 mM PMSF, 5 gg/mL Pepstatin A, 0.025% bacitracin, and 3 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In competition studies, membranes (0.02 mg) were incubated with 0.1 nM of [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.

WO 99/06397 PCT/US98/15479 Example Inhibition ETA at 1 1D 2 3 4 6B 7 8 9 14 16 17 18 19 21 22 23 26 27 28 29 31B 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 -728- Table 4 Binding Data Example 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 52 54 55 56 57 58 59 60 61C 62 63 Inhibition ETA at 1 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 WO 99/06397 WO 9906397PCT/US98/15479 -729- Example Inhibition ETA at 1 64 66 67 68 691D 71 72C 73C 74 76 79 82 83 84 86 87 88 89 91 C 92C 93C 96 9-7 95.0 82.8 87.7 96.3 84.6 37.4 62.7 81.4 80.7 96.3 95.6 95.3 93.1 100.4 89.4 90.3 85.0 65.3 52.6 62.4 84.3 84.6 91.6 107.4 59.2 82.1 86.1 89.0 Example 98 99 100 101 102 103 104 105 106 107 109 110 111 112 113 114 115 116 117 118 119 120 121 122 125 126 127 128 Inhibition of ETA at 1

PM

86.8 92.1 76.8 89.2 75.2 69.0 98.0 98.6 90.0 97.2 96.8 94.4 101.8 94.9 94.3 86.2 88.4 79.3 95.2 93.2 86.6 99.5 98.6 95.3 97.2 91.7 91.4 95.4 WO 99/06397 PCTIUS98/15479 00 Cl -730- Example Inhibition Example Inhibition of ETA atl1 of ETA atl1 00gmg 123 89.7 156 92.6 N 2 9. 578.

0012910178.

0129 100.1 158 91.8 Cl130 91.0 159 36.2 131 89.5 160B 80.3 132 90.0 161 93.6 133 88.6 162B 91.5 134 92.2 163 90.6 135B 77.7 164 98.6 136 79.4 165 54.1 138 83.0 166 91.6 139 98.6 167 94.4 140 106.3 291 100.0 141 92.8 293 89.8 142B 78.7 294 77.7 143 20.6 295 93.0 144 78.2 296 87.1 145 32.4 297 84.4 146 25.0 298 93.3 147 73.0 299 90.4 148 94.7 300 96.1 149 84.6 301 96.7 150 93.6 302 86.6 151 80.5 303 87.2 152 86.9 304 89.7 153 97.1 305 87.4 154 80.2 306 93.3 155 92.7 307 92.2 WO 99/06397 PCT/US98/15479 00 -731- Example Inhibition Example Inhibition of ETA at 1 of ETA ati1 00 RM g 308 93.0 351 99.0 Ni 309 80.7 352 96.2 00 0310 87.1 353 73.7 0311 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 82.2 363 82.3 322 95.6 365 59.2 323 91.3 366 91.5 324 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 WO 99/06397 WO 9906397PCTIUS98/1 5479 -73 2- Example 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 Inhibition ETA at 1 95.7 96.8 91.4 79.4 86.2 47.8 98.7 69.2 100 98.2 45.6 93.7 100 97.8 79.8 98.7 100 90.0 59.9 93.0 96.5 80.5 96.1 95.4 86.4 94.5 100 Example 408 409 410 411 412 413 414 415 416 417 418 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 Inhibition of ETA at 1

PM

100 89.4 91.4 93.5 86.4 99.5 91.4 87.3 86.4 98.7 100 100 100 96.6 89.1 85.8 90.8 97.2 100 100 100 94.1 99.1 95.5 99.6 100 97.8 WO 99/06397 WO 9906397PCTIUS9SII 5479 -733- Example 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 Inhibition ETA at 1 100 100 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 Example Inhibition ETA at 1 459 460 461 462 463 464 465 466 467 468 469 470 471 475 476 477 479 495 496 497 498 499 500 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 WO 99/06397 WO 9906397PCTIUS98II 5479 -734- 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 WO 99/06397 PCT/US98/1 5479 00 e -735- SAs 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 oo hydrolysis was measured.

6 Determination of Phosphatidvlinositol (PI) Hydrolysis SMMQ cells (0.4 x 106 cells/mL) were labeled with 10 pCi/mL of N 3 H]myo-inositol in RPMI for 16 hours. The cells were washed with PBS, then incubated with Buffer A containing protease inhibitors and mM LiCI for 60 minutes. The cells were then incubated with test compounds for 5 minutes, and then challenged with 1 nM ET-1. ET-1 challenge was terminated by the addition of 1.5 mL of 1:2 (v/v) chloroform-methanol. Total inositol phosphates were extracted after adding chloroform and water to give final proportions of 1:1:0.9 (v/v/v) chloroform-methanol-water as described by Berridge (Biochem. J. 206 587-595 (1982)). The upper aqueous phase (1 mL) was retained and a small portion (100 gL) 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.

WO 99/06397 PCT/US98/15479 -736- Table Phosphatidylinositol Hydrolysis Example IC50 uM 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 o00 0.0012 534 0.05 553 0.0004 s Table 6 ETA/ETB Selectivity MMQ cells, porcine cerebellar tissues (known to contain ETB receptors) and chinese hamster ovary cells (CHO) permanently transfected with the human ETA or ETB receptor were homogenized in ml of 10 mM Hepes (pH 7.4) containing 0.25 M sucrose and a protease inhibitor [50 mM EDTA 0.1 mM PMSF, 5 Ig/ml Pepstatin A, and 0.025% Bacitracin] using a micro ultrasonic cell disruptor. The mixture was centrifuged at 1000xg for 10 min. The supernatant was collected and 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 WO 99/06397 PCT/US98/15479 00 O -737- Scontaining 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 diluted oo -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 ig/mL Pepstatin A, 0.025% bacitracin, and 50 mM EDTA) to a final concentration of 0.2 mg/mL of protein. In oo competition binding studies, membranes (0.02 mg) were incubated with O 0.1 nM of [1251]ET-1 (for ETA assay in MMQ or CHO cells transfected c 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 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 pIM ET-1. IC50 values are calculated using an average of at least two separate determinations. The data shows the selectivity of the compounds of the invention in binding to the endothelin receptors.

Table 6 EXAMPLE rET-A rET-A pET-B Selectivity hET-A hET-B Selectivity NO. IC50 IC50 (rA/pB IC50 IC50 (hA/hB 1pM) (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 WO 99/06397 WO 9906397PCTILIS98/15479 738- 507 S08 509 510 511 512 513 514 515 516 517 518 519 520 521 523 524 525 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 3.0 >100,000 >33,000 1.63 >100,000 1 .9 0.56 0.50 0.81 0.42 0.30 1 .0 1 .6 0.71 1.0 1.3 0.38 0.20 0.67 0.42 0.79 8.2 45,000 30,000 35,000

N.D.

>80,000 8,800 26,000 >62,000 29,000 30,000 85,000 14,000 28,000 37,000 360 1,700 560 23,000 53,000 68,000 >190,000 29,000 26,000 >37,000 40,000 30,000 63,000 36,000 130,000 54,000 880 2,100 2.1 0.51 1 .0 0.60 0.58 0.36 0.36 6.7 1 .8 0.43 0.31 0.23 0.33 0.82 51,000 23,000 11 ,000 15,000 60,000 14,000 9,800 100,000 37,000 12,000 38,000 19,000 290 890 >60,000 24,000 45,000 11 ,000 25,000 102,000 37,000 29,000 15,000 21,000 29,000 124,000 83,000 880 1,100 WO 99/06397 PCT/US98/15479 -739- 100 96.6 98.3 98.1 99.8 100 97.9 10,000 43,000 6,300 1,300 3.800 1,700 17 7,400 440 1,200 0.71 100 97.2 97.3 100 5.1 3,200 76 7,900 0.12 0.36 0.52 17,000 0.96 5,900 100 3.0 33,000 6,200 0.08 0.92 0.23 630 0.28 52,000 1,900 40 22,000 560 56,000 8,200 >96,000 136,000 0.78 7100,000 7125,000 1.0 >96,000 0.26 42,400 160,000 0.29 39,500 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: 739 WO 99/06397 PCT/US9/15479 00 -740- 0 %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.

oo 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 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 740 WO 99/06397 PCT/US98/15479 -741- Buffer B (final volume: 0.2 ml) in the presence of increasing concentrations of unlabeled test ligands for 4 hours at 25C. 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 pM ET-1.

Figure 1A.

so ;f 10 1C [Example 43], M >98% Protein Bound Figure IB. Figure IC.

120 100 o IC0

I

H 2% 0% 2% 2.0 nM \20 6.5 nM S 3.1 nM 5.0 nM S 5.5 nM 0 5% 5.0 nM 1o0 10* 10' 10 10-" 10" 10"' 10' E Example 53P0, M Sproein oun78 Protein Bound 10 Figure 1 Inhibition of 12 S11ET-1 binding to human ETA receptor by ETA antagonists. Each curve was determined in the presence of either or 5% HSA, and WO 99/06397 PCT/US98/15479 00 assays were performed as described above. The results are expressed as of G control binding, with 125 1I]ET-1 binding in the absence of antagonist defining S 100%. Each point represents the mean of three determinations.

As observed in Figure 1A, a compound which is highly protein bound (Example 4 00 S 98% bound) shows a rightward shift of the binding curve (toward decreasing potency S in the presence of increasing albumin levels. The compound of Example 531 (Figure 1B N in which protein binding is reduced to 92%, shows a substantial diminution of this 00 0 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 retain high affinit 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 3.55 742 /OlW7101 PrT/n 1R/1i 5479 00 743- The present invention provides less protein bound compounds having S 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 00 protein may be reduced by attaching a counterbalanced charge at a biologically acceptab S site. For example, protein binding is reduced by attaching a "basic" functionality (group N^ which carry a positive charge at physiological pH) on the amide sidechain (see Formula 00 wherein R 3 has an amide sidechain).

The present invention covers compounds having the formula XII: R2 Z R3

(CH

2 )n

R

XII

wherein Z is -C(R 1 8

)(R

19 or wherein R18 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(o) 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(0)NHR17 wherein R 1 7 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(0)NHS(0)2R16 wherein R16 is loweralkyl, haloalkyl, aryl or dialkylamino, WO 99/06397 PCT/US98/15479 00 -744- (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is-defined as above,

HO

0 00 (n) 00 ()HO 0 ~00 (p)0 0

~NH

0

N

HN(

0

H

N

Mt H or

(U)

Rl 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, alkylsulonylamidoalkyl, 744 WO "/06397 PCT/US98/15479 00 -745-

C

2 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;

R

3 is (a)R 4 -C(0)-R 5

R

4 -C(0)-R 5 N(Re)-, wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 or 00 -R 8 a-N(R 20 )-RB wherein R 8 and R 8 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-R1 9 or -Rga0R 9 wherein R 9 and Ra are independently selected from alkylene; c-9a 00 10 R 4 and R 6 are (Rll)(Rl 2 wherein Rj 1 and R 12 are independently selected f rom c-I(1) hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, (11) heterocyclic, (12) arylalkyl, (1 3) (heterocyclic) alkyl, (14) hydroxyalkyl, (1 5) alkoxy, (16) aminoalkyl, (1 7) trial kylaminoalkyl, (1 8) alkylamino 'al kyl, (19) dial kylami noalkyl, carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocycliclaminoalkyl, and (heterocyclic) aminoalkyl, with the proviso that at least one of and R, 2 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, alkylaminoalkyl, dial kyl aminoal kyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic) aminoalkyl, and (heterocyclic) alkylaminoalkyl; or a pharmaceutically acceptable salt thereof.

WO 99/06397 PCIUS98/1 5479 00 -746- Preferred compounds having reduced protein binding are shown in Table 9A wherein R may be selected from the substituents shown in.Table 9B.

c-i Table 9A.

00 OCH 3 OCH3 OCH 3 N R.N R.N ci"COOH "COOH

CO

00 c- 0 0 1 2 0 3 0.)

OCH

3 R. N R. R.N CO CC COOH

COOH

-l0 -0 4l 5 CH 3 O __j "COOH *N ROO N COOii CNC CI R. N R. N HR. N "CO

OO*..

0 0 0HO o 0 12 0 746

I

WO 99/06397 WO 9906397PCTIUS98/I 5479 747 WO 99/06397 PCT/US98/1 5479 -748- 28 R. N

(NJ

NNH

31 CH 3 0 O- Table 9B.

H

3 CNH NFf.

0 4 0 7 H

H

10 0 13 H 0 16 0 748 HCNH,,e,,,,N 2 0 5 0

H

8 0 H 0

H

14 0 17 0

H

3 CNH Ny 3 0

H~T

6 0 9 0

H

12 0 15 0 18'Y 0 WO 99/06397 PCTIIJS98/1 5479 -749- 19 H 0 22 0 28 31 r 2 0 0 0 0 34 37 0 43 460- 2 HN> 0 49 0 2

HN,)

20> 0 23 0

Y/-

26 0 ft 3 CNN', 29 0 32 0 0 (CHh)3N.lNk 35 0 38C 41 0 47 0 CH3N 0 53 21 24 0 27 0 30 0 0 33 0 36 39 0 420 0 0 0 480) HN> 0

ON

51 0 749 WO 99/06397 PCT/US98/15479 WO 99/06397 PCTIUS98/1 5479 00 -750-

CH

3 N o 0 0 ooo 55 56CH3N.2 57 6106 H 030 0058 00 58 59K~UM-ti 60~~ 1~

H

61Or62 H 63~- 0) 00 0 64

H

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.

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. 10 131 (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).

WO 99/06397 PCT/US98/15479 00 -751- The ability of the compounds of the invention to treat myocardial ischemia can Sbe 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 0 o (1984).

The ability of the compounds of the invention to treat cerebral vasospasm can 0 be demonstrated according to the methods described in Nakagomi, et al., J.

o0 Neurosurg. 66 915 (1987) or Matsumura, et al., Life Sci. 49 841-848 (1991).

The ability of the compounds of the invention to treat cerebral ischemia can N 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).

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).

I

WO 99/06397 PCT/US98/15479 00 -752- SThe ability of the compounds of the invention to treat LPL-related lipoprotein Sdisorders 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 0 o Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi, et al., Biochem. Biophys. Res. Comm. 191840-846 (1993); and Shichiri, et al., J. Clin.

SInvest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle oo proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or CI 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 pulmonary hypertension can be demonstrated according to the method described in Bonvallet et al., Am. J. Physiol. 266 H1327 (1994). Pulmonary hypertension can be associated with congestive heart failure, mitral valve stenosis, emphysema, lung fibrosis, chronic obstructive pulmonary disease (COPD), acute repiratory distress syndrome (ARDS), altitude sickness, chemical exposure, or may be idiopathic.

The ability of the compounds of the invention to treat plaletet aggregation, and thrombosis, can be demonstrated according to the method described in McMurdo et al. Eu. J. Pharmacol. 259 51 (1994).

The ability of the compounds of the invention to treat cancers can be demonstrated according to the method described in Shichiri, et al., J. Clin. Invest. 87 1867 (1991).

The ability of the compounds of the invention to treat IL-2 (and other cytokine) mediated cardiotoxicity and vascular permeability disorders can be demonstrated according to the method described in Klemm et al., Proc. Nat. Acad. Sci. 92 2691 (1995).

The ability of the compounds of the invention to treat nociception can be demonstrated according to the method described in Yamamoto et al., J. Pharmacol.

Exp. Therap. 271 156 (1994).

The ability of the compounds of the invention to treat colitis can be demonstrated according to the method described in Hogaboam et al (EUR. J.

Pharmacol. 1996, 309, 261-269).

752 WO 99/06397 PCT/US98/15479 00 -753-

S

The ability of the compounds of the invention to treat ischemia-repurfusion Sinjury in kidney transplantation can be demonstrated according to the method Sdescribed 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 00 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 O derived from inorganic or organic acids. These salts include but are not limited to 0o the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesufonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, c cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogencontaining groups can be quatemized 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, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other WO 99/06397 PCT/US98/15479 00 -754-

O

representative organic amines useful for the formation of base addition salts include Sdiethylamine, 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 oo useful (in a human or other mammal) for the treatment of hypertension, acute or chronic pulmonary hypertension, Raynaud's disease, congestive heart failure, O myocardial ischemia, reperfusion injury, coronary angina, cerebral ischemia, cerebral o0 vasospasm, chronic or acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced CN 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.

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 754 WO 99/06397 PCT/US98/15479 00 -755of transdermal administration such as transdermal patches or iontophoresis devices.

SThe term parenteral as used herein includes subcutaneous injections, intravenous, Sintramuscular, intrasternal injection, or infusion techniques.

SInjectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing 0 o or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally O acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among oo the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are Sconventionally 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 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 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 755 WO 99/06397 PCT/US98/15479 00 -756- (Ni like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), Sboth 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.

oo A representative solid dosage form, for example, a tablet or a capsule, comprises: SCompound of the invention: 35% w/w oo Starch, Pregelatinized, NF 50% w/w Microcrystalline Cellulose, NF 10% w/w o( Talc, Powder, USP 5% w/w While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents.

Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, !0 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.

756 WO 99/06397 PCT/US98/15479 00 -757- Representative potassium channel activators include pinacidil and the like or Sa 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.

00 0The compounds of the invention and the cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses.

C) Dosage levels of the active compounds in the compositions of the invention may be 00oo 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.

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 !0 claims.

Claims (61)

1. A compound of the formula: 00 R2 zNR3 (CH 2 )n R) 00 (NRi wherein Z is -C(R18)(R 19 or wherein R 18 and R19 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)M-W wherein m is an integer from 0 to 6 and W is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -ON, -C(O)NHR 17 wherein R 17 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 o, (in) -S(O) 2 NHC(O)Rl 6 wherein R 16 is defined as above, HO 0 0 WO 99/06397 PCT/US98/15479 00 -759- ci( 0 HO 0 OH 000 (p) 0 00 NH (q)0 .k-e 0 (t'H ,0o NHS 2 CF R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alky lam inocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arytalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsutonylamidoalkyl, 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; WO 99/06397 PCTIUS98/15479 00 -760- R 3 is (a)R4-C(O)-R 5 R4-R5'a-, R4-C(O)-Rs- N(R 6 R6-S(O) 2 -R 7 or R26-S(O)-R 2

7- wherein Rs is -a covalent bond, (ii) alkylene, (iii.) alkenylene, (iv) -N(R 20 or RaN20R8 wherein R 8 and R8a are independently selected from the group 0050 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 aO0R 9 wherein R 9 and Ra are independently selected from alkylene; 00 R5a is alkylene or (ii) alkenylene; R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 21 )-Rl 0 or -RlOa-N(R21)-Rio- wherein Rio and Rica are independently selected from the group consisting of alkylene and alkenylene and R 21 is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl; R4 and R6 are independently selected from the group consisting of (Ril)(Rl 2 wherein R 1 1 and R12 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) trialkylamninoalkyl, (18) alkylaminoalkyl, WO 99/06397 PCT/IJS98/15479 00 -761- CI(19) dialkylaminoalkyl, and carboxyalkyl loweralkyl, c-I(iii) alkenyl, alkynyl, 00 cycloalkyl, (v i) cycloalkylalkyl, aryl, (viii) arylalkyl, 0090 (ix) heterocyclic, (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (xiv) haloalkenyl, (xv) haloalkoxyalkyl, (xvi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, 100 (xix) dialkylaminoalkyl, (xx) alkoxy, and H (CHzNN R7a (xx i) 0 wherein z is 0-5 and R7a is alkylene; 105 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 R 27 is alkylene or alkenylene; 110 R 22 -O-C(O)-R 23 wherein R2 2 is a carboxy protecting group or heterocyclic and R 23 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(R 24 )-R 25 wherein R 25 is alkylene and R 24 is hydrogen or loweralkyl, loweralkyl, WO 99/06397 WO 9906397PCT/US98/15479 -762- 115 120 125 alkenyl, alkynyl, Mf cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic) alkyl, (in) alkoxyalkyl, alkoxyalkoxyalkyl, R13-C(O)-CH(Rl 4 wherein R 13 is amino, alkylamino wherein R 15 is amino, or a pharmaceutically acceptable or or dialkylamino and R 1 4 is aryl or alkylamino or dialkylamino; salt thereof. 2. The compound according to Claim 1 wherein n is 0 and Z is -CH 2 3. The compound according to Claim 1 wherein n is 1 and Z is -CH 2 4. The compound according to' Claim 1 wherein n is 0, Z is -CH 2 and R 3 is R 4 -C(O)-R 5 R 6 -S0 2 -R 7 or R 26 -S(O)-R 27 wherein R 4 R 5 1 R 6 7 R 7 R 26 and R 27 are as defined therein. The compound according to Claim 1 wherein n. is 0, Z is -CH 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 R26-S(O)-R 27 wherein R 7 is alkylene, R 27 is alkylene and R 6 and R 26 are as defined therein. WO 99/06397 PCT/US98/15479 00 -763 N7. The compound according to Claim 1 wherein n is 0, Z is -C H 2 and R 3 is R 4 -C(O)-N(R 20 )-R 8 or R 6 -S(O) 2 -N(R 21 )-Rl 0 wherein R 8 and Rio are alkylene and R 4 R 6 R 20 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 00 gruorRi erzl oRis-()NS02 whriR grou orRi erzllo s-()NSO 2 16 whri 1 6 is loweralkyl, haloalkyl or aryl, Z is -OH 2 RI and R 2 are independently selected from loweralkyl, (ii) cycloalkyl, (iii) substituted and 00 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 wherein R 4 is (Rll)(R12)N- wherein Rjj and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoal kyl, trialkylaminoalkyl, aryl and arylalkyl and R 5 is alkylene; or R 3 is R 4 -C(O)-N(R 20 )-R 8 or R 6 -S(Q) 2 -N(R 2 1 )-R 10 wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and Rio are alkylene 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 R 1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl,* phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or u nsubstituted 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 WO 99/06397 PCT[US98/15479 00 -764- c-ior dihydrobenzofuranyl whe'rein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1I,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- 00 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 2 l)-Rlo- wherein R 8 and RIO 0 are alkylene, R 20 and R 21 are loweralkyl, R 4 is loweralkyl, aryl, alkoxy, oo 20. alkylamino, aryloxy or arylalkoxy and R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl. 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 16 is loweralkyl, haloalkyl or aryl, Z is -CH 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-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 alkoxy, alkoxyalkoxy and carboxyalkoxy, (ix) arylalkyl, aryloxyalkyl, (xi) heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-1 ,4-benzodioxanyl, 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 Ri11 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, WO 99/06397 PCT/US98/15479 00 -765- Cltetrazolyl or -C(O)-NHS(O) 2 R, 6 wherein 11 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 R 1 is loweralkyl (ii) alkenyl, (iii) arylalkyl, (iv) aryloxyalkyl, heterocyclic, (vi) heterocyclic (alkyl), (vii) aryl, (viii) Cl (N-alkanoyl-N-alkyl)aminoalkyl, or (viii) alkylsulfonylamidoalkyl, R 2 i substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy- 1,3- 00 benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, l1 fluorophenyl or difluorophenyl wherein the substituent is selected from c-i loweralkyl, alkoxy and halogen and R 3 is R4-C(O)-R 5 wherein R5 is 00 alkylene and R 4 is (Rii)(Ri 2 wherein R 11 is loweralkyl, and R 12 i 0 aryl or arylalkyl.

12. The compound according to Claim 1 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 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 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 R3 is R6-S(O) 2 -N(R 2 l)-RlO- wherein Rj 0 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl.

13. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl or aryl, Z is -CH 2 Rl 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 WO 99/06397 PCT/US98/15479 00 -766- c-i and alkoxyalkoxy, R 2 is Substituted or unsubstituted 1 ,3-benzodioxolyl, 7methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-i14- lo enzdioanyl, dihydrobenzofuranyl, 4-methoxyphenyl, N- 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 )-Rlo- wherein R 10 is alkylene, R 6 is 00 loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl and R 21 Is loweralkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl. 00

14. The compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R 1 6 wherein 11 16 is loweralkyl or haloalkyl, Z is -CH 2 RI is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 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 R. 5 is alkylene and R 4 is (Rii)(Rl2)N- wherein RI, and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. 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 or haloalkyl, Z is -CH 2 Rl 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 R5 is alkylene and R 4 is (Ril)(R 1 2 )N- wherein R 1 1 and R 12 are independently selected from loweralkyl, aryl hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, heterocyclic, and arylalkyl. WO "/06397 PCT[US98/15479 00 -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 -C H 2 R 1 is substituted or unsubstituted 4-methoxyphenyl, 4- c-I fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, I ,4-benzodioxanyl or 00 dihydrobenzofuranyl wherein the substituent Is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 114- benzodioxanyl, d ihyd robe nzof uranyl, benzofuranyl, 4-methoxyphenyl, od 10 dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-Rs- wherein RS is alkylene and R4 is (Rji)(Ri2)N- wherein Rjj and R 1 are c-I 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 -CH 2 R, is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,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, Io dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rll)(R 12 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 -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 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1,4- WO 99/06397 PCT/US98/15479 00 -768- benzodioxanyl, dihydrobenzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl wherein the su bstituent is selected from loweralkyl, alkoxy and halogen and R 3 is ci R4-C(O)-R5- wherein R 5 is alkylene and R 4 is (Rll)(Rl 2 wherein RI, is alkyl and R 12 is selected from aryl, aminoalkyl,- trial kylIami noalkyl, 00 15 and heterocyclic.

19. A compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is 00 -CH 2 R1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyl-N-alkyl)aminoalkyl, or c-i alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R4 is (Rll)(Ri2)N- wherein Rjj and R 12 are independently selected from alkyl, aryl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. A compound according to Claim 1 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, Z is -CH 2 R 1 is loweralkyl,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 and R4 is (Rnj)(R12)N- 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.

21. The compound according to Claim 1 of the formula: R2 ZN..,R3 101, K (H2)n wherein Z is -C(Rl 8 )(Rl 9 or wherein R 18 and R 19 are independently selected from hydrogen and loweralkyl; n isO0 or 1; WO 99106397 PCTIUS98/1 5479 00 -769- R is -(CH2)M-W wherein m 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 ci(c) -P(O)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -ON, -C(O)NHR17 wherein R17 is loweralkyl, 00 Cs 15 alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, 00 hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 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 o)HO 0 OH (p) 0 0 0 WO "/06397 PCTIUS98/15479 COO -770- A-IJL N *S H (j-CF3 00 30 Mt ,or NHSO 2 CF 3 (u) 00 Rl and R 2 are independently selected from hydrogen, loweralkyl, 0 alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, c-I 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 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; R 3 is R 4 -C(O)-R 5 R4-R~a, R6-S(O) 2 -R 7 or R26-S(O)-R 27 wherein R 5 is a covalent bond, (ii) alkylene, (iii) alkenylene, (iv) -N(R 20 )-R 8 or wherein R 8 and Raa 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-R 9 or -R 9 a-O-R 9 wherein R 9 and R9a are independently selected from alkylene; is alkylene or (ii) alkenylene; R7 is a covalent bond, (ii) alkylene, (iii) alkenylene or (iv) -N(21-Ro-or -RlOa-N(R21)-RlO- wherein Rio and R10a 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 Rr. are independently selected from the group consisting of WO 99/06397 PCT/US98/15479 00 -771- Ni (Rii)(Ri 2 wherein R11 and R12 are independently selected from hydrogen, loweralkyl, haloalkyl, 00 alkoxyalkyl, CI 65 haloalkoxyalkyl, alkenyl, alkynyl, 00(8) cycloalkyl, cycloalkylalkyl, (10) aryl, (11) heterocyclic, (12) arylalkyl, (13) (heterocyclic)alkyl, (14) hydroxyalkyl, (15) alkoxy, (16) aminoalkyl, and (17) trialkylaminoalkyl, (i i) loweralkyl, (iii) alkenyl, (i v) alkynyl, cycloalkyl, (v i) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) he-terocyclic, (heterocyclic)alkyl, (x i) alkoxyalkyl, (xii) hydroxyalkyl, (xiii) haloalkyl, (x iv) haloalkenyl, (xv) haloalkoxyalkyl, (x vi) haloalkoxy, (xvii) alkoxyhaloalkyl, (xviii) alkylaminoalkyl, WO 99/06397 PCT/US98/15479 00 -772- N- 95 (xix) dialkylaminoalkyl, (xx) alkoxy, and (CH2$\ N~ R (xxi) 0 wherein z is 0-5 and R7a is alkylene; c-I R 26 is loweralkyl, (ii) haloalkyl, (iii) alkenyl, (iv) alkynyl, (v) 00 0 cycloalkyl, (vi) cycloalkylalkyl, (vii) aryl, (viii) arylalkyl, (ix) c-i heterocyclic, (heterocyclic)alkyl, (xi) alkoxyalkyl or (xii) alkoxy- substituted haloalkyl; and 105 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 25 wherein R 25 is alkylene and R24 is hydrogen or loweralkyl, 110 loweralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, 115 aryl, arylalkyl, aryloxyalkyl, heterocyclic, (heterocyclic)alkyl, 120 (in) alkoxyalkyl, alkoxyalkoxyalkyl, or R13-C(O)-CH(Rl 4 wherein R1 3 is amino, alkylamino or dialkylamino and R 14 is aryl or R15-C(O)- wherein R1 5 is amino, alkylamino or 125 dialkylamino; or a pharmaceutically acceptable salt thereof. WO 99/06397 PCT/US98/15479 -CH 2 -773-

22. The compound according to Claim 21 wherein n is 0 and Z is

23. The compound according to Claim 21 wherein n is 1 and Z is -CH2-.

24. The compound according to Claim 21 wherein n is 0, Z is -CH 2 and R 3 is R 4 R 6 -S0 2 -R 7 or R 26 -S(O)-R 27 wherein R 4 R 5 R 6 R 7 R 26 and R 27 are as defined therein. The compound according to Claim 21 wherein n is 0, Z is -CH 2 and Rs is alkoxyalkyl or alkoxyalkoxyalkyl.

26. The compound according to Claim 21 wherein n is 0, Z is -CH 2 and R 3 is R 4 wherein R 4 is (R11)(R 2 as defined therein and R 5 is alkylene or R 3 is R 6 -S(0) 2 -R 7 or R26-S(0)-R27- wherein R 7 is alkylene, R 27 is alkylene and Re and R 26 are as defined 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 20 )-R 8 or R6-S(0) 2 -N(R 2 1)-Rio- wherein R 8 and R 10 are alkylene and R 4 R 6 R 20 and R 21 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 16 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 R4-C(O)-R 5 wherein R 4 is (R11)(R 12 wherein R 1 j and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, WO 99/06397 PCT/US98/15479 00 -774- N- heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, aryl and arylalkyl and is alkylene; or ci R 3 is R4-C(O)-N(R 20 )-R 8 or wherein R 4 is loweralkyl, aryl, alkoxy, alkylamino, aryloxy or 00 20arylalkoxy and 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl, R 8 and R 10 are alkylene and R 20 and R 21 are loweralkyl; or 00 R 3 is R 6 -S(O) 2 -R 7 or R 26 -S(O)-R 27 wherein R 6 is loweralkyl or haloalkyl, R7 is alkylene, R 26 is loweralkyl and R 2 7 is alkylene.

29. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 R, 6 wherein R 1 6 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-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) 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-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)-N(R 20 )-R 8 or R-S(O) 2 -N(R 2 l )-R 1 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 WO 99/06397 PCT/US98/15479 00 -775- c-I R 6 is loweralkyl, haloalkyl, alkoxyalkyl, aryl or arylalkyl. The compound according to Claim 21 wherein n is 0, R is cN -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 00 aryl, Z is -CH2-, Ri is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) C' 5 cycloalkyl, phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- c-i ethoxyphenyl, 4-ethyiphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 00 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-alkanoyi-N-alkyl)aminoalkyl, or (xiii) alkylsulfonylamidoalkyl, R 2 is substituted or unsubstituted 1,3- benzodioxolyl, 7-methoxy-1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, 8- methoxy-l1,.4-benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4- methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and A3~ is R4-C(O)-R5- wherein R5 is alkylene and R4 is (R11)(R12)N- wherein R 11 and R 12 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl and arylalkyl, heterocyclic, hydroxyalkyl, alkoxy, aminoalkyl, and trialkylaminoalkyl.

31. The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 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 R4-C(O)-Rs- wherein IRS is alkylene and R4 is (Rll)(Rl 2 wherein RI, is loweralkyl and R 12 is aryl or arylalkyl. WO 99/06397 PCT/US98/15479 00 -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 -CH 2 R 1 is phenyl or (ii) substituted or unsubstituted 4- methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluorophenyl, 3-fluoro- 00 4-ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 1,3- benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, 00 alkoxyalkoxy and carboxyalkoxy, R 2 is substituted or unsubstituted 1,3- 0 10 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 21 )-Rl 0 wherein R 10 is alkylene, R 6 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl and R21 is loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl or arylalkyl. 33 The compound according to Claim 21 wherein n is 0, R is -C(O) 2 -G wherein G is hydrogen or a carboxy protecting group, tetrazolyl or -C(O)-NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl.*or aryl, Z is -OH 2 RI 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 ,4-benzodioxanyl, 8-methoxy-1,A- 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 )-Rl 0 wherein R 10 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, WO 99/06397 PCT/US98/15479 00-77 tetrazolyl or -C(O)-NHS(O)'R 16 whri 16 is loweralkyl or haloalkyl, Z is -CH2-, R 1 is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, c-I 4-pentafluoroethyiphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, 00 alkoxyalkoxy and carboxyalkoxy, R 2 s1,-ezdooy,14 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-RS- 00 wherein R5 is alkylene and R 4 is (Rii)(Rl 2 wherein R11 and R 12 are independently selected from loweralkyl, aryl arylalkyl, hydroxyalkyl, cI alkoxy, aminoalkyl, trialkylaminoalkyl, and heterocyclic. 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 or haloalkyl, Z is -CH 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 R3 is R4-C(O)-R 5 wherein R. 5 is alkylene and R 4 is (Rii)(Rl 2 )N- wherein Rjj and R 12 are independently selected from loweralkyl, aryl, arylalkyl, hydroxyalkyl, alkoxy, aminoalkyl, trialkylaminoalkyl, and o heterocyclic.

36. The compound according to Claim 21 wherein n is 0, R is -C(O)2-G wherein G is hydrogen or a carboxy protecting group, Z is -OH 2 RI is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, 2-fluorophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 4-ethylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from alkoxy, alkoxyalkoxy and carboxyalkoxy, R 2 is 1 ,3-benzodioxolyl, 1,4- benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R3 is R4-C(O)-R 5 wherein R 5 is alkylene and R 4 is (Rli)(Rl 2 wherein Rjj and R 12 are independently selected from loweralkyl. WO 99/06~397 PCTJINQJ 15479 00 -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 R1 is substituted or unsubstituted 4-methoxyphenyl, 4- fluorophenyl, '2-fluorophenyl, 4-methyiphenyl, 4-trifluoromethyiphenyl, 4-pentafluoroethylphenyl, 4-methoxymethoxyphenyl, 4-hydroxyphenyl, 00 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-benzodioxolyt, 1,4- 00 benzodioxanyl, dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, fluorophenyl or difluorophenyl and R 3 is R4-C(O)-R 5 ci wherein R5 is alkylene and R4 is (RII)(Ri2)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 -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 ,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 RIO 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 -CH 2 R 1 is loweralkyl,alkenyl, heterocyclic (alkyl), aryloxyalkyl, aryalkyl, aryl, (N-alkanoyi-N-alkyl)aminoalkyl, or alkylsulfonylamidoalkyl, and R 3 is R 4 -C(O)-R 5 wherein R, 5 is alkylene WO 99/06397 WO 9906397PCTIUS98/1 5479 -779- 00 w0 00 and R4 is (Rii)(Ri 2 wherein Rj 1 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 R3 is R4-C(O)-R 5 wherein R5 is alkylene 0o and R 4 is (Rii)(R12)N- wherein RI, 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

41. A compound selected from the group consisting of trans- trans-2- Methoxp he nyl) (1 ,3-be nzod ioxo175-y1) -1 propyl-N-n-pentanesulfonylamino)propyl]pyrrolidine-3. carboxylic acid; trans, trans-2-(4-Methoxymethoxyphenyl)-4-(1 1 2 -(N-propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol -5-yl)-1 propyl-N-n-pentanesulfonylamino)ethyl]pyrrolidine-3- o carboxylic acid; trans, trans-2-(3,4-Dimethoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1 (N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine.3 carboxylic acid; trans,trans-2-( 4-Propoxyphenyl)-4-(1 ,3-benzodioxol-5-y)-1 p ropy l-N-n-pentanes ulfonylamino)ethyl]pyrrolidine-3carboxyI ic acid; trans, trans-2-(3,4-Dif luorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(3 ,4-Difluorophenyl)-4-(1 ,3-benzodioxol-5-yl)-1 o p ropy I-N-n-pe ntanes u fo nyla mino)ethyl]pyrro Iid ine-3carboxy ic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4(1 1 2 -(N-propyl-N-n-hexanesulfonylamino)ethyl]pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 00 -780- N- 25 trans, trans-2-(3- Flu oro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-B-yI)- 1 2 -(N-propyl-N-(3-chloropropanesuIto nyl) am ino)ethy I) pyrrolidine-3-carboxylic *acid; N- trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-( 1,3-benzodioxol-5-yI)- 1 -(2-(N-isobutyl-N-(3- 030 chloropropanesulfonyl)amino)ethyt)pyrrolidine-3carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -[2-(N-propyl-N-(4- methylbutanesulfonyl)amino)ethyl]pyrrolidine3carboxylic acid; 00 -trans, trans-2-(4-Methoxy-3-fluoropheny)-4-(7-methoxy.1 ,3- 0 35 benzodioxol-5-yi)-1 -[2-(N-propyl-N-(n- c-i 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)ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(1 ,4-Benzodioxan-6-yI)-4-(7-methoxy- 1,3-benzodioxol- 1 -[2-(N-propyl-N-(n- pentanesulfonyl)amino)ethyllpyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-isobutyl-N-(pentanesulfonylamino)ethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4.(1 1 -(2-(N-(2-methoxyethyl)-N-(3-chloropropanesulfonyl)amino)- ethyl)pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 1 -(2-(N-(2-methoxyethyl)-N- (penMan esulIf ony1) am ino)ethyl)pyrro lid ine-3-carboxyl ic acid; trans, trans-2-(3-Fluo ro-4-methoxyphenyl)-4(1 1 2 -(N-propyl-N-((2,2,2-trifluoroethoxyethane)sulfonyl)amino)- ethyl]pyrrolidine-3-carboxylic acid; trans, trans-2-(3-Fiuoro-4-methoxyphenyI)-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- WO "/06397 PCT/US98/15479 00 -781- N~ 60 m eth y Ipro panes uIf o nyI)am Ino)ethy] pyrroI id ine-3-ca rboxygic acid; and trans, trans-2-(3-Fluoro-4-methoxyphenyl)-4-(1 ,3 c-i1 -(2-(N-isobutyl-N-(butanesulfonylamino))ethyl)pyrrolidine-3 carboxylic acid; trans, trans-2-(2-Methylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 00 di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethylpentyl)-4-(1 ,3-benzodioxol-5-yI)-1 di(n-butyI)aminacarbony~methy)-pyrrolidine-3-carboxyijc acid; 00 trans, trans-2-(2-(1 ,3-Dioxo-2-yI)ethyl)-4-(1 ,3-benzodioxol-5-yl)-1 0 70 (NN-di(n-buty)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Tetrahydro-2H-pyran)ethyl)-4-(1 ,3-benzodioxol- -yI)-1 -(NN-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)-pyrrolidine-3. carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(1 ,3- benzodioxol-5-yI)-1 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-fluorophenyl)] 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,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-fI uoro-3-methylphenyl))aminocarbonylmethyl). pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid; WO 99/06397 PCT/US98/15479 00 -782- (2S, 3R, 4S)-2-(2,2-Di methylpe ntyl)-4-(7-methoxy- 1 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3 carboxylic acid c-i trans, trans-2-(2-(*1,3-DioxoI-2-yI)ethyl)-4-(7-methoxy-1 ,3- )o benzodioxol-5-yi)-l-(N-4-heptyl-N-(4..fluoro-3- methyiphe nyl))aminocarbo nylmethyl)-pyrrolidine-3-carboxylic 00acd acid trans, trans-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1 0 yI)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- (N 00 carboxylic acid; trans, trans-2-(2,2-dimethylpenty)-4-(2,3-dihydro-benzofuran-5-yl)- 1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3- carboxylic acid; trans, trans-2-(2,2,-Dimethyl-2-(1 ,3-dioxolan-2-yI)ethyl)-4-(7- methoxy-1 1 3-benzodioxol-5-yI)-1 -(NN-di(n- butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid; trans, trans-2-(2-(2-Methoxyphenyl)-ethyl)-4-(7-methoxy- 1,3- benzodioxol-5-yI)-1 N-di (n-butyl) aminocarbo nyl methyl)- pyrrolidine-3-carboxylic acid; trans, trans-2-(2,2-Dimethyl-3-(E)-pentenyl)-4-(7-methoxy-1 ,3- benzodioxol-5-y)-1 -(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-3-carboxylic acid; 120 (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-l1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3- carboxylic acid; (2S, 3R, 4S)-2-(2-(2-oxopyrrolidin-1 -yI)ethyl)-4-(1 yI)-1 -(N-4-heptyl-N-(4-fluoro-3- 125 methylphenyt))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; WO 99/06397 PCT/US98/15479 00 -783- trans, trans-2-(4-Methoxyphenyl)-4-(1 ,3-beflzodioxol-5-yl)-1 butyl-N-(4-dimethylaminobutyl)amino)carbonylmethyl]. pyrrolidine-3-carboxylic acid; N(2R,3R,4S)-2-(3-Fluoro-4-methoxyphenyl).4(1 l1-( 2 -(N-propyl-N-pentanesulfonylamino)ethyl)-pyrrolidine-3 carboxylic acid; 00 (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(1 di(n-butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; 0(2S,3R,4S)-2-(2,2-Dimethylpent-(E)-3-enyl).4.(1 00 00 yl)-1 -(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine.3 0 carboxylic acid; (2S, 3 R,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)-methyl)-4(1 1 -(NN-di(n-butyl)aminocarbonylmethyl)pyrrolidine3carboxylic acid; and (2S,3R,4S)-2-(2-(2-Methoxyphenyl)ethyl).4(1 ,3-benzodioxol-5-yI)-1 N-di(n-butyl)aminocarbonylmethyl)pyrrolidine.3carboxylic acid; D or a pharmaceutically acceptable salt thereof. 4 2; A compound of the formula: NH (CH 2 )n (CH 2 )m wherein n is 0 or 1; m is 0 to 6; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 H 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -CN, WO "/0O6397PTISI157 PCrfUS98/15479 -784- 00 00 -C(O)NHR 17 where R 1 7 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O)2RI6 where R 16 is loweralkyl, haloalkyl, phenyl or dial ky lam in a, (in) -S(O) 2 NHC(O)Rl 6 HO 0 .t -VN0 HO 0 OH 0N 0 0 0 H H ,or WO 99/06397 PCT/US98/15479 -785- 00 NHSO 2 CF 3 an R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl,. haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, 00 cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alyaioabnlakl ilyaincroyakl yaminocarbonylalkyl, alkylaninocarbonylalkyl, c- 3 dayaminocarbonylalkenyl, hrxalk enyl, aryl, arylalkyl, 0 0 aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, N- 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.

43. The compound of Claim 42 wherein m 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.

44. The compound of Claim 42 wherein n and m are both 0; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; and 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-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 WO 99/06397 PCT/US98/15479 -786- 00 O S difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen; or o2 the substantially pure or (-)-isomer thereof. The compound according to Claim 42 of the formula: 0 R2R21, 00 H NH V( (cH2)n 4 (CH2)n (CH 2 )m (CH 2 oo I I 0 W R1 W R1 or wherein n is 0 or 1; m is 0 to 6; W is -C(0)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 R17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(0) 2 R 16 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, -S(0)2NHC(O)R 16 HO NH o WO 99/06397 PCTIUS98/15479 -787- 00 OH 0 NH 000 0 0 00~ N N- CF 3 LNHSO 2 CF 3 NH0C3 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, (heteirocyclic)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.

46. The compound according to Claim 45 wherein m is zero or 1;- WO 99/06397 PCTfUS98/15479 -788- 00 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 mn are both 0; W is -CO2-G wherein G is hydrogen or a carboxy protecting group; 00 and R1 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-trifluoromethylphenyl, 00 4-pentafluoroethyiphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ci 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 ?0 the substantially pure or (+)isomer thereof.

48. The substantially pure compound (+)-trans,trans-2-(4- Methoxyphenyl)-4-(1 3 -benzodioxo-5-lyl)pyrrolidine-3-carboxylic acid; or a salt or ester thereof.

49. The substantially pure compound (2S,3R,4S)-2-(2,2- Dimethylpentyl)-4-(7-methoxy-1 .3-benzodioxol-5-yl)-1-(N,N-di(n- butyl)aminocarbonylmethyl)-pyrrolidine3carboxylic acid; or a salt or ester thereof. WO 99/06397 PCT/US98/15479 WO 9/0637 PT/USS/1 479-789- 00 A compound of the formula R 2 N'-R~b (cpH 2 n (C H2)m T 00 w wherein n is 0 or 1; mnis 0to 6; 00 R, is alkylene; 0 is a leaving group; W is -C(0) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 H- 2 -P(0)(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(0) 2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dial kylImin o, (in) -S(0) 2 NHC(0)Rl 6 HO 0 (0) WO 99/06397 PCT/US98/15479 -790- 00 OH 00INH 000 0H 04 SN H, 0 an R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, -alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alky lam inocarbonylalkyl, dialky lam inocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)NRc wherein Raa is aryl or aryIalkyl, Rbb is hydrogen or alkanoyl and R C is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; or a salt thereof. WO 99/06397 PCT/US98/15479 -791- 00

51. The compound according to Claim 50 wherein m is zero or 1; R 5 b, is alkylene; Q is a leaving group; and W is 7CO 2 -G wherein G is hydrogen or a carboxy protecting group; or the substantially pure or (-)isomner thereof. 00

52. The compound according to Claim 50 wherein n and m are both 0; N- R5b is alkylene; 00 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- ethoxyphenyl, 4-ethylphenyl, 4-methyiphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4- ethoxyphenyl, 2-fluorophenyl, 4-methoxymethoxyphenyl, 4- hydroxyphenyl, 4-t-butylphenyl, 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and 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 R2N. R5bQ R~b Q (CH2)m (CH 2 )m W R or w R WO 99/06397 WO 9906397PCTIUJS98II 5479 -792- 00 10 00 N~ 15 wherein n is 0 or 1; m is 0 to 6; is alkylene; Q is a leaving group; W is -C(O) 2 -G where G is hydrogen or a carboxy protecting group, -P0 3 H 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR 17 where R 17 is loweralkyl, alkylamninocarbonyl, dialkylamninocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 R 1 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 OH "IN 0 0 WO 99/06397 PCT/US98/15479 -793- 00 oO c- 'o o s= o 00 H CF3 00 or 0 NHS0 2 CF 3 and R1 and R2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (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 1 and R 2 is other than hydrogen; or a salt thereof.

54. The compound according to Claim 53 wherein m is zero or 1; 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; R5b 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- WO 99/06397 PCTIUS98/15479 -794- 00 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-benzodioxa nyl or dihydrobenzofuranyl wherein the substituent is selected from loweralkyl, haloalkyl, alkoxy, alkoxyalkoxy and carboxyalkoxy and R 2 is 00 substituted or unsubstituted 1 ,3-benzodioxolyl, 7-methoxy-1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl, 8-methoxy-1 ,4-benzodioxanyl, C) 15 dihydrobenzofuranyl, benzofuranyl, 4-methoxyphenyl, dimethoxyphenyl, 00 -fluorophenyl or difluorophenyl wherein the substituent is selected from loweralkyl, alkoxy and halogen, (ix) aryalkyl, aryloxyalkyl, (xi) CI heterocyclic (alkyl), (xii) (N-alkanoyl-N-alkyl)aminoalkyl, or (xiii) alkysulfonylamidoalkyl; or the substantially pure or (+)isomer thereof. WO 99/06397 PCT/US98/15479 00 -795-

56. A compound of the formula R 2 N' R5b -NHR2~a (CH 2 )n (CH 2 )m 00 w wherein n isO0 or 1; m is 01to6; R5b is alkylene; hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, 00 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 0 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyl, -ON, -C(O)NHR 17 where R 17 is loweralkyl, alkylaminocarbonyl, dialkylaminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 where R16 is loweralkyl, haloalkyl, phenyl or o1 dialkylamino, (in) -S(O) 2 NHC(O)Rl 6 HO 0 0 ()HO x 0 OH I-IN WO 99/06397 PCT/US98/15479 00 -796- N 25 0, 000 (r 0 00N H J~ CF 3 M H or NHSO 2 CF 3 an R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyt, cycloalkyl, cycloalkylalkyl, amninocarbonylalkyl, 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 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; is hydrogen, loweralkyl, alkenyl, haloalkyt, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cyctoalkylalkyl, aryl or arylalkyl; and WO 99/06397 PCT/US98/15479 -797- 00 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; 00 R~ 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; NI and R1 is loweralkyl, (ii) alkenyl, (iii) alkoxyalkyl, (iv) cycloalkyl, 00 0 phenyl, (vi) pyridyl, (vii) furanyl or (viii) substituted or c-i 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 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 2 Oa R2C 1, RSb N N I I W R o r W WO 99/06397 PCT/US98/15479 -798- 00 wherein n is 0 or 1; m is 0 to 6; R.5b 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 o r a carboxy protecting group, -P03H 2 -P(O)(OH)E where E is hydrogen, loweralkyl or arylalkyt, 00 -O N, -C(O)NHR 17 where R 17 is loweralkyl, alkylaminocarbonyl, 00(g) dialkylaminocarbonyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 where R 16 is loweralkyl, haloalkyl, phenyl or dialkylamino, (in) -S(O)2NHC(O)Rl 6 HO 0 0 HO 0 OH (p) 0 (q) IvN 0 WO 99/06397 PCT/US98/15479 00-79 ct Al NA H CF 3 00 H or NHSO 2 CF 3 00 and R 1 and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyt, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, arytox-yalkyl, arylalkoxyalkyl, (N-alkanoyl-N- alkyl)aminoalkyl, alkylsulfonylamidoalkyl, heterocyclic, (heterocyclic)alkyl and (Raa)(Rbb)NRc 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. The compound according to Claim 59 wherein m is zero or 1; is alkylene; R20a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyt, 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. WO 99/06397 PCT/US98/15479 -800-

61. The compound according to Claim 58 wherein n and m are both O; R5b is alkylene; R 20 a is hydrogen, loweralkyl, alkenyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; W is -CO 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) 00 substituted or unsubstituted 4-methoxyphenyl, 4-fluorophenyl, 3-fluorophenyl, 4- ethoxyphenyl, 4-ethylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4- 00 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)- WO 99/06397 PCT/US98/15479 -801- O 4-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier. c' 10 65. A pharmaceutical composition for antagonizing the action of endothelin comprising a therapeutically effective amount of (2S,3R,4S)-2-3-Fluoro-4- 00 methoxyphenyl)-4-(1,3-benzodioxol-5-yl)-1 -(2-(N-propyl-N-pentanesulfonyl)ethyl)- S pyrrolidine-3-carboxylic acid and a pharmaceutically acceptable carrier. 00 -N 66. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

67. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.

68. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1- (N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.

69. A method for antagonizing the action of endothelin comprising administering to a mammal in need of such treatment a therapeutically affective amount of (2S,3R,4S)-2-3-Fluoro-4-methoxyphenyl)-4-(1 ,3-benzodioxol-5-yl)-1-(2- (N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, WO 99/06397 PCT/US98/15479 00 S-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. oo

71. A method for treating coronary angina, cerebral vasospasm, acute and S chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, N endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative 00 Sdiseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, C 5 IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.

72. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfusion injury, angina, pulmonary hypertension, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21.

73. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4- (7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)- pyrrolidine-3-carboxylic acid.

74. A method for treating hypertension, congestive heart failure, restenosis following arterial injury, renal failure, cancer, colitis, repurfursion injury, angina, WO 99/06397 PCT/US98/15479 00 -803- O 0 pulmonary hypertension, prostatic hyperplasia, migraine, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such Streatment 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. oo o c 75. A method for treating coronary angina, cerebral vasospasm, acute and oo Schronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxicity, c endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 21.

76. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, ischemia-repurfusion injury, Raynaud's disease, prostatic hyperplasia, and migraine comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy- 1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid.

77. A method for treating coronary angina, cerebral vasospasm, acute and chronic renal failure, gastric ulceration, cyclosporin-induced nephrotoxocity, endotoxin-induced toxicity, asthma, LPL-related lipoprotein disorders, proliferative WO 99/06397 PCT/US98/15479 00 -804- 0 diseases, acute or chronic pulmonary hypertension, platelet aggregation, thrombosis, IL-2 mediated cardiotoxicity, nociception, colitis, vascular permeability disorders, Sischemia-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- 00 benzodioxol-5-yl)-1 -(2-(N-propyl-N-pentanesulfonyl)ethyl)-pyrrolidine-3-carboxylic acid. 0 oo I 78. A method for treating treating hypertension, congestive heart failure, restenosis following arterial injury, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1 in combination with one or more cardiovascular agents.

79. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 21 in combination with one or more cardiovascular agents. A method for treating treating hypertension, congestive heart failure, cerebral or myocardial ischemia or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of (2S,3R,4S)-2-(2,2-Dimethylpentyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)- 1-(N,N-di(n-butyl)aminocarbonylmethyl)-pyrrolidine-3-carboxylic acid in combination with one or more cardiovascular agents. 1 WO 99/06397 PCT/US98/15479 -805-

81. A process for the preparation of a compound of the formula: 00 00 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 CO 2 E wherein E, R 1 and R 2 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, 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. WO 99/06397 PCT/US98/15479 00 -806- 0 84. The process of Claim 71 wherein E is loweralkyl, R, is 4-methoxyphenyl and R 2 is I A process for the preparation of a compound of the formula: 00 00 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, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dialkylaminocarbonylalkenyl, aryl, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (N-alkanoyi-N-alkyl)aminoalkyl, alkylsuffonylamidoalkyl, 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. WO 99/06397 PCTIUS98/15479 00 -807-

86. The process of Claim 75 wherein E is loweralkyl, R, is arylI 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. 00

588. The process of Claim 75 wherein E is loweralkyl, R, is N0 4-methoxyphenyl and R 2 sI,-ezdoo--I 89. A process for the preparation of a compound of the formula: R 3 7 C0 2 E wherein E is a carboxy-protecting group, 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 and R 3 is R 4 -C(O)-R 5 wherein R 5 is alkylene and R 4 is (R 1 1 )(Rl 2 wherein R 1 I and R1 2 are independently selected from loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, WO 99/06397 PCT/US98/15479 0 -808- alkenyl, S(6) alkynyl, cycloalkyl, cycloalkylalkyl, aryl, oo (10) heterocyclic, (11) arylalkyl and c 25 (12) (heterocyclic)alkyl; 00 oo 0 (13) hydroxyalkyl, N (14) alkoxy, aminoalkyl, and (16) trialkylaminoalkyl, or a salt thereof, comprising a) catalytic hydrogenation of a compound of the formula: O 2 N R 2 R1 CO 2 E 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)NR11R 12 wherein R11 and R 12 are independently selected from the group consisting of loweralkyl. I WO 99/06397 PCT/US98/15479 00 -809- O 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 00 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 S halogen or sulfonate leaving group. 00 93. A process for the preparation of the substantially pure (+)-trans,trans optical isomer of the compound of the formula: R2 aR, CO 2 E wherein E is loweralkyl, R 1 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 compound of the formula: R2 Rj CO 2 E 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. WO 99/06397 WO 9906397PCT/US98/I 5479 00 -810- 94. A compound of the formula: 00 (CH 2 )n wherein Z is -C(RlB)(Rl 9 or wherein R 18 and Rj 9 are independently selected from hydrogen and loweralkyl; n is 0 or 1; R is -(CH2)m-W wherein mn is an integer from 0 to 6 and W is -C(0) 2 -G wherein G is hydrogen or a carboxy protecting group, -P0 3 1- 2 -P(0)(OH)E wherein E is hydrogen, loweralkyl or arylalkyl, -CN, -C(O)NHR 17 wherein R 17 is loweralkyl, alkylaminocarbonyl, dial kyl aminocarbonyl, tetrazolyl, hydroxy, alkoxy, sulfonamido, -C(O)NHS(O) 2 Rl 6 wherein R 16 is loweralkyl, haloalkyl, aryl or dialkylamino, (in) -S(O) 2 NHC(0)Rl 6 wherein R 16 is defined as above, WO 99/06397 WO 9906397PCT/US98/I 5479 00 HO 0 0 00 00(o) HO 0 OH ~N 0, (r) NN\ N >CF3 H or (u)2CF Rl and R 2 are independently selected from hydrogen, loweralkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, haloalkyl, WO 99/06397 WO 9906397PCT[US98/15479 00 -812- haloalkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkoxyalkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, alkylamino'carbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylalkenyl, alkylaminocarbonylalkenyl, dial kylaminocarbonylalkenyl, hydroxyalkenyl, aryl, arylalkyl, aryloxyalkyl, 00 C arylalkoxyalk~yl, (N-alkanoyl-N-alkyl)aminoalkyl, alkylsulonytamidoalkyl, heterocyclic, (heterocyclic) al kyl and (Raa)(Rbb)N-Rcc- wherein Raa is aryl or 00 arylalkyl, Rbb*d Is hydrogen or alkanoyl and R C is alkylene, with the proviso that one or both of R, and R 2 is other than hydrogen; R 3 is (a)R4-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(R0CR8 wherein R 8 and R8, 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 RO R 9 wherein R 9 and R 9 a are independently selected from alkylene; R 4 and R 6 are (13 11 1 2 wherein Rl 1 and R 1 2 are independently selected f rom hydrogen, loweralkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, WO 99/06397 WO 9906397PCT/US98/I 5479 00 -813- (11) heterocyclic, (12) arylalkyl, (heterocyclic)alkyl, (14) hydroxyalkyl, 00(15) alkoxy, (16) aminoalkyl, (17) trial kylaminoalkyl, 00 0(18) alkylaminoalkyl, ci(19) dial kylaminoal kyl, carboxyalkyl, (21) (cycloalkyl)aminoalkyl, (22) (cycloalkyl)alkylaminoalkyl, (23) (heterocyclic) aminoalkyl, and (24) (heterocyclic) aminoal kyl, with the proviso that at least one of R 1 and R 12 is selected from heterocyclic, aminoalkyl, alkylaminoalkyl, dial kyl ami noal kyl, trialkylaminoalkyl, alkylaminoalkyl, dial kyl aminoal kyl, carboxyalkyl, (cycloalkyl)aminoalkyl, (cycloalkyl)alkylaminoalkyl, (heterocyclic) aminoalkyl, and (heterocyclic) alkylaminoal kyl; or a pharmaceutically acceptable salt thereof. I1 WO 99/06397 PCT/US9815479 -814- A compound selected from the group consisting of: WO 99/06397 PCT/US98/15479 -815- 00 00 WO 99/06397 PCT/US98/15479 -816- 31 O 2 and 32 wherein R is selected from the group consisting of: H CNH N~ 1 0 H3CNH,_,,- ,N 4 0 "-N 13 H 0 H 16 0 H3CNH,,-,,,N-trl 2 0 5 H 0 8 0 H 0 14 0 SN N 17 H 0 H 3 CNH-L- NL 3 0 6 0 9 H 0 H 12 0 15 0 18'* 0 WO 99/06397 WO 9906397PCT/US9815479 -817- 190 22,0{ 0 23 0 ~r 21 H 0 240 0 -rl 0 (H3C2N 0 2( 2S 3: 0 0 0 0 ftC)2,,, 0 0 0 (CH 3 N---Nl-J 34S.- 0 37 0 43 0 2 HN,,) 0 33 0 36 (CH N 2 39 0 42 OQ 0 38 ON 0 471N 0 C8N 0 53M, 0 0 ON 0 480---) HN'T 0 0 WO 99/06397 PCT/US98/15479 00 O -818- (NNO 00 610 62 H 63o- ,and CH N 0 0 HN 0N"^ 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, OINr NN'kY N "N'k 'N N S58LPL-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. 62 63 64 97. A method of improving hypertension, congestive heart failure, restenosis follreducing arterial injury, renal failure, cancer, colitis, repurfusion amount of compound bound to protein by attachinjury, a chargedina, functionality hypertension, migraine, cerebral or myocardial isched.ia, 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. WO 99/06397 PCT/US98/15479 00 -819- 98. A method of claim 97 wherein the charged functionality carries a positive charge at physiological pH. 00 00 CO o